Clearing the Air on Residual Solvents

The i's have been dotted, and the t's have been crossed. After years of revisions, debates, and delays, the USP General Chapter 467 Residual Solvents will finally take effect on July 1, 2008. Although most large, multinational pharmaceutical companies have been preparing for these requirements for some time, there is still a significant portion of the industry, especially smaller firms, that are either not aware of how USP ‹467› will change their analytical practices or are in denial that the standards will directly affect them.

Many raw materials used to manufacture pharmaceutical products contain residual solvents at various levels. Because USP ‹467› applies to all compendial drug substances, excipients, and products, this chapter influences all aspects of the industry. Despite the preparation and even after several workshops and conferences on the topic, confusion and questions remain about where the solvent limits actually apply, how the methods should be established, when the data should be reported, and what information is required from ingredient suppliers. To help answer these questions, industry experts and regulators are collectively encouraging analysts to pay attention to the details in the chapter.

Background and application

The new USP ‹467› chapter replaces the previous ‹467› "Organic Volatile Impurities" (OVI) chapter established in 1990. Although the OVI chapter specified several methods for monitoring seven highly toxic solvents, it omitted many other industry solvents. Moreover, the methods were based on direct-injection gas chromatography (GC). In direct injection, the GC autosampler needle dips into the liquid, takes up liquid, and shoots the solution onto the GC. "This technique is hard on the GC because you are injecting not only the volatiles but also the API, which is typically not volatile. That is the way it was done because there simply wasn't a better way to reliably sample for these volatile impurities," says Jon Brice, PhD, director of pharmaceutical services at BioScreen Testing Services (Torrance, CA). "Ultimately it wasn't very effective," agrees Neil Schwarzwalder, global compendial consultant, Global Quality Laboratories, at Eli Lilly and Company (Indianapolis, IN).

In 1997, the International Conference on Harmonization (ICH) published Q3C, "Impurities: Guideline for Residual Solvents," which provides guidance for 59 residual solvents. Before the US Food and Drug Administration approved the ICH guideline in 1997, manufacturers had only the OVI general chapter to go by, and there was no general guideline on residual solvents. At that time, manufacturers conducted their own toxicology assessments of the solvents that they used for new products. The ICH guideline was uniform, and manufacturers had a standard that they could meet for new products. It did not apply to existing products, however. "The industry was in a situation where they were applying one standard to the new materials, another standard for older materials, and perhaps for really old products, no standard," says Schwarzwalder.

For harmonization, the new USP ‹467› chapter is patterned closely after the ICH Q3C guideline. The latest revision was published in December 2007 and was meant to correct the final points of disagreement. "USP, the industry, and FDA have worked very hard to resolve those differences," says Larry Ouderkirk, director of Compendial Operations Staff at FDA/CDER/OPS-IO. " I believe now what we've got in the latest version of ‹467› is something that is virtually identical to Q3C. I don't think there's any substantive differences left that haven't been addressed, and I think industry is now satisfied that the differences have been resolved."

There are regulatory differences, however, between USP ‹467› and ICH Q3C. ICH Q3C is a guideline, which means it is not enforceable. Currently, it applies to new drug applications (NDAs) and abbreviated new drug applications (ANDAs) approved after 1997 and applications that reference it. USP ‹467› is a mandatory drug standard according to the Food, Drug, and Cosmetic Act of 1938. It applies to all compendial drug products; that is, products with a USP monograph.

Figure 1: Identifying residual solvents and testing procedures.

"There are a lot of drug products that are approved by the agency that do not have a USP monograph, but the NDA and ANDA are still reviewed by the agency and even though there is no requirement in USP necessarily for residual solvents, we always review all drug applications to make sure residual solvents are tested for, and ICH Q3C guidance is still fully applicable to those drug products that perhaps do not have a monograph in USP," says Ouderkirk.

USP ‹467› and ICH Q3C categorize residual solvents, including those previously under the OVI chapter, into three classes according to their toxicity level (see sidebar, "Residual solvents classifications"). Both documents assess the risk to human health according to permitted daily exposure (PDE), which differs from the terminology used by the International Program on Chemical Safety (which uses "tolerable daily intake") and the World Health Organization (which uses "acceptable daily intake"). Both documents also list concentration limits (in ppm) for Class 1 residual solvents and limits (in ppm concentration and PDE) for Class 2 residual solvents. Questions about these limits, including how they are calculated and where they apply, are widespread.

Clarification on limits

Understanding the difference between the limits in terms of PDE and the limits in terms of concentration (in ppm) has turned out to be one of the most crucial areas of understanding USP ‹467›. Those who have followed the evolution of the general chapter are quick to urge readers to read the text very carefully.

The text states that the chapter applies to existing drug substances, excipients, and products, and that all substances and products are subject to relevant control of solvents likely to be present in a substance or product. As Delwyn Schumacher, principal chemist in the Methods Development Department at Lancaster Laboratories (Lancaster, PA), observes, "that statement pretty much means that if a solvent is used in a drug-related manufacturing process, it [the solvent] needs to be evaluated one way or another in the produced material for compliance with the applicable limits."

Residual solvents classifications*

One key point that industry experts, regulatory agencies, and ingredient suppliers are making, however, is that the limits specified in ‹467›, including those listed for Class 2 residual solvents, apply only to the finished drug product. The current misinterpretation is that these limits apply to the individual ingredients of the drug product.

"Specifications in Class 2 solvents is an area where there is a lot of confusion and is probably the biggest concern we have from an excipient perspective," says David Schoneker, director of global regulatory affairs at Colorcon (West Point, PA) and Chair of IPEC-Americas. "A lot of people have not really read it. They look at the Class 2 limits, where it lists a particular solvent, and think it's the maximum level you can use in any ingredient. They then go to suppliers and say they can't use it if it's higher than that level. There are many excipients that commonly have those residual solvents with levels that are higher than those listed in the table, and there is no problem with that because the levels are for the drug product and not for the individual ingredient."

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One of the ways to demonstrate that the finished product complies with the specifications is by knowing the residual solvent information for the various components of the formulation, that is, the excipients as well as the active pharmaceutical ingredient (API).

"You have to go back and look at your ingredients," says Schwarzwalder. "The USP chapter does apply to the excipients in your product and to the API, but only through the product. That was a distinction that was missing in the OVI requirement that USP applied previously. You can have an ingredient that has a higher level of Class 2 solvent in it, if it's necessary, provided that when you take that ingredient and mix it into the product you don't go over the final limit. You have the flexibility to formulate your product in an appropriate manner and without applying an arbitrary standard to each individual ingredient."

Calculating the options

USP ‹467› provides concentration limits for Class 1 solvents, which as noted in the text should not be used in the manufacture of drug substances, excipients, and finished product. In addition, the chapter considers Class 3 solvents in amounts of 50 g per day or less to be acceptable without justification. Most of the solvents fall under the Class 2 category.

Option 1. Key to understanding the limits for Class 2 solvents is understanding that they were calculated using what ICH and USP call the "Option 1" method. This method uses the listed PDE value in mg per day for a given Class 2 residual solvent, and calculates the concentration ppm limits according to the equation:

Concentration (ppm) = (1000 mg/mL × PDE)/dose

This calculation applies for any daily dose that is equal to or less than 10 g. According to USP ‹467›, "If all drug substances and excipients in a formulation meet the limits in Option 1, these components may be used in any proportion. No further calculation is necessary provided the daily dose does not exceed 10 g." This option also allows manufacturers to skip the need to test the final drug product for residual solvents if the raw materials suppliers report that their product is below the listed limits.

Of course, not every formulation will have all of its components fall within the Option 1 limits. "There are a lot of high-quality excipients that have specifications in the USP monograph higher than those levels, and because it's a residual from the manufacturing process the level would not be easy to lower," says Schoneker. "That doesn't mean there is anything wrong or that the process used to make that excipient has to change. If you read through what it says in both the ICH document and the USP document, it clearly says you can use excipients with levels that are higher than those listed in the Class 2 levels table. You just have to use the Option 2 calculation."

Option 2. The Option 2 calculation takes into account that for many formulations, a given drug substance or excipient may be only a very small component of the final drug product. In such a case, the PDE value for each component can be calculated using the equation under Option 1 and then the total PDE value can be added. If the total PDE value for the drug product is below the specification listed in the Class 2 Residual Solvent table, then the drug product meets the specification.

"If your drug is extremely potent and you are going to give much less of it, then you are actually allowed to have a higher amount of solvent as a percentage because the amount of drug you are giving overall is much less," says Dr. Jon Brice. "This is why it is a risk-based approach. Instead of saying the specification is 100 ppm and there is no discussing it, you are allowed to take other things into consideration. A solvent may be higher than the specification when you test your API, but if you are not using very much of it, and it is going into a formulation that will be given not very often, then it might be that by the time you get to the drug product your overall limit is not that high."

Testing the final drug product. Sometimes during processing, a residual solvent is driven off, such as by drying or evaporation, so a final drug product could end up with a lower residual solvent content than the calculated predicted value. In that case, the finished drug product can be tested directly. "What you are really accountable for is what comes out at the end from a solvents perspective," says Dr. Jon Brice. "Solvents are known impurities. It's not like doing an HPLC [high-performance liquid chromatography] impurities test, where there could be compounds that you've never seen before. Everyone knows where the solvents come in their methods, and we have a lot of GC [gas chromatography] methods that are dedicated to just solvent identification and quantitation."

Contract analysts worry, however, that some of their pharmaceutical company clients are relying too much on drug-product testing. "We're finding these methods weren't designed to perform that well for some finished products," says Schumacher, who suggests it is best to monitor and conduct as much testing as possible on API and excipients before the finished product. "Once it is finished product, many times you have mixed solubility issues with the various product components, and in this situation the method doesn't necessarily work very well."

Methods and modifications

Unlike ICH Q3C, USP ‹467› includes an analytical testing methods section, "Identification, Control, and Quantification of Residual Solvents." Not surprisingly, the recommended methods are based on headspace GC flame-ionization detection (GC-FID). GC-FID has been known for at least the past 10 years to be more efficient, accurate, and gentler on the column than direct-injection techniques.

For Class 3 residual solvents at or below the 5000 ppm concentration limit (solvent limit ≤50 mg/day), USP ‹467› refers to "‹731› Loss on Drying" (LOD) for cases in which the monograph for an article contains an LOD procedure. For a few specific monographed items, however, analysts can apply the monograph LOD to monitor Class 3 solvents. "It's a small fraction of all the excipients and other drug substances. It's certainly less than 5%," says Schumacher. "Before the revisions to ‹467›, it was common practice to correct LOD results for moisture content by an alternate technique such as Karl Fischer to obtain residual solvents data, but this is no longer an acceptable practice."

USP ‹467› says that other Class 3 residual solvents should be identified and quantified using methods outlined for Class 1 and Class 2 solvents "with appropriate modifications." But, this may not be easy. "It's not as simple as just running Class 1 and Class 2," says Schumacher. "Companies may find all of a sudden that they are in a position where they need results and they may not have performed the background or have the lab do the background work to develop a method or validate a method to cover their other residual solvents needs. Without a specific monograph saying you can use loss on drying, they are not going to be able to, and [companies] have been used to doing that to cover their bases on Class 3 compounds."

The methods outlined for Class 1 and Class 2 residual solvents can be complex, as some analysts suggest. USP ‹467› outlines three procedures (Procedures A, B, C), prepared differently for water-soluble versus water-insoluble articles, all based on GC-FID.

"The concept here is procedure A is running the work on one specific column, and procedure B is running on an orthogonal column," says Schumacher. "Some compounds will elute better on one versus the other, which laboratories need to give some consideration as well, depending on what compound lists are submitted. And then the C procedure is the true quantitative procedure. A and B are actually semi-quantitative procedures. Their results are acceptable proof negative. If solvent results are below applicable limits, then you don't need to do any further testing. If any solvent exceeds one of the limits, then procedure C applies, which is actually a single-point method of additional spiking of a sample matrix to detemine a quantitative value. You do not need to run procedure A, B, and C in a circumstance where you know what compound list you are looking for. If you have a definiticve compound list and you know what you need to monitor, in theory you can go right to procedure C."

One laboratory has helped its clients understand better the various methodologies by categorizing the list of Class 2 solvents even further, referring to "mix A," "mix B" and "mix C" compounds (1). As Schumacher observes, "The reality is that the prescripted testing only covers a very narrow range of compounds. Only the Class 1 and Class 2 mix A and Class 2 mix B compounds have specific scripted tests," says Schumacher. "Once you run into Class 2 mix C and Class 3, the methodology is not specifically established. So some level of validation will be required," adds Travis Emig, director of pharmaceutical chemistry at Lancaster Laboratories.

One group of Class 2 solvents, however, "are not readily detected by headspace injection conditions," as described in the chapter. As mentioned previously, testing may need to be developed or modified for monitoring Class 3 compounds as well, and sample matrix issues may not allow direct application of ‹467› methodology. For these reasons, USP ‹467› leaves room for manufactures to develop "other appropriate validated procedures," and analysts need only to test for the solvents that are "likely to be present."

Analysts will be the first to make note of the modifications that will help guide the development of these appropriate validated methods."What a lot of what people have found is that there are problems with running <467> verbatim," says Schumacher. "We found problems with running on some headspace systems because specific wording in <467> conflicts with manufacturer design. As 467 is written, procedure A allows the use of a more-narrow bore-diameter column but procedure B does not. I've seen application notes for running <467> that basically have columns that aren't allowed in <467>."

Residual impact

The effect on excipient suppliers. "The best way to control solvents is to control your processes, know your supplier, understand, and try to limit the amount of solvent that you use to what you really need," says Schwarzwalder.

This means that excipient companies will need to share a lot more information about their process and their material residual levels than they had previously. "Some small pharma companies and generics houses haven't really talked to their suppliers about how these materials are made," says Schoneker. "These companies then have to scramble to get better information from their suppliers than they had done in the past."

The problem that arises is that companies tend to develop exhaustive, sometimes irrelevant, questionnaires for their suppliers. "Suppliers are getting different questionnaires from every customer and asking different questions—some are reasonable and some about issues that don't really matter," says Schoneker. "You have to have this balance. How do you share information in a reasonable way so that you get what you need without putting the excipient supplier in a situation where they are having to do a huge amount of work to supply their customers with information they consider confidential?"

IPEC is working on excipient qualification guidelines, which focus on technical and GMP qualification and information and understanding how much information companies need to meet the requirements. IPEC's Excipient Information Protocol has a section on residual solvents and discusses the need for the supplier to incorporate the key information that is needed to use the material and meet the residual solvents guideline.

The effect on OTC manufacturers. Some over-the-counter (OTC) products also may fall under the USP ‹467› requirements. "A lot of these issues are always positioned in terms of Rx-type products, but there is a whole other business area that often gets overlooked," says Tine Engel, PhD, principal scientist at The Procter & Gamble Company (Mason, OH). In general, OTCs contain a lot more excipients and ingredients because consumers are interested in taste, mouth feel, and so forth, which require additional nontherapeutic ingredients in formulations.

OTC products with USP monographs fall under the requirements in USP ‹467›. Other OTCs may be approved under an NDA or ANDA but do not have a USP monograph. "In these cases, we will probably continue to apply the ICH Q3C guideline," says Ouderkirk.

Engel and other OTC analysts largely support the USP ‹467› changes. "I think they are good rules. The fact that USP has harmonized with ICH means we don't have to make up different rules for products that we sell at different global locations. What people may not realize is that we are working with a lot of different materials and at bigger quantities. It takes more raw materials to make a tube of toothpaste than a pill. And we do have to be very careful to set up good systems because normally consumers are more exposed to many of our products. You may take a pill once a day, but you brush your teeth two or three times a day. Any additional testing that is required hits us doubly hard. Of course it is very important to protect the safety of the consumer, but we need to do it in a way that isn't going to put OTC companies out of business."

Retesting concerns. Manufacturers that choose not to pay close attention to the requirements may undergo costly consequences. "One of the things we see almost every time a USP revision comes out is that there is always a group of products that have been tested according to an older version of USP, and then if they don't immediately employ their (raw) material in the manufacture and it sits in a warehouse while the USP changes, they all of a sudden are stuck in a situation where they are trying to use material that is now out of spec," says Dr. Jon Brice. If a manufacturer tests its raw material according to a USP monograph, uses it in manufacture and then USP changes, the company is grandfathered in. However, if a company tests its raw material and then the material sits in storage and during that time the USP changes, then they simply can't use that material in manufacturing because the company must test according to the USP that is in effect when manufacture begins and must retest.

Next steps

Implementation for USP ‹467› was pushed back from July 1, 2007 to July 1, 2008 to allow the industry time to prepare. But even so, analysts worry it may not be enough time. "The regulations have been changed so much and it's been so drawn out that I've got a feeling that a lot of people are behind on this and they are going to be in scramble mode real soon," predicts Schumacher.

FDA plans to issue a Federal Register notice that would clarify when compliance with the USP ‹467› specifications should be reported. A draft is in the works and is currently undergoing the approval process. For products that are already marketed under an NDA or ANDA, manufacturers would report their compliance with USP ‹467› in the next annual report. "I don't think we will require them to include a lot of analytical detail in the annual report," says Ouderkirk. "For example, they may have developed methodologies to comply with ‹467›, and rather than having supplements filed we're just looking to an annual report for them to notify us that they are compliant. We are trying to avoid triggering a lot of supplements from the industry." New NDAs should take ‹467› requirements into consideration. "If I were filing something today, I would want to note that I am complying with ‹467› no later than July 1," says Ouderkirk.

Other organizations also are planning to help clarify the lingering concerns about methods, applications, and changes brought about by USP ‹467›. At its annual scientific meeting in September, USP hosted a track section solely on the issue of residual solvents, and additional training sessions are in the works. Several pharmaceutical laboratories are also planning and sponsoring events and offer their expertise on validated methodologies. These efforts are timely and, apparently, in great need. "I would say it's really about a 50–50 mix of pharmaceutical companies that are fully on board with what is going on here, with 50% that are behind the 8 ball and not really understanding what their responsibility is going to be with this. From a client perspective it seems like some folks haven't kept up with what's going on as to how this has changed," says Emig.

Reference

1. Lancaster Laboratories, internal publication on USP ‹467›, available at

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