Maribel Rios

's have been crossed. After years of revisions, debates, and delays, the 

 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 

‹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 

 ‹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.  

 ‹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 

 (Torrance, CA). "Ultimately it wasn't very effective," agrees Neil Schwarzwalder, global compendial consultant, Global Quality Laboratories, at 

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. 

 ‹467› chapter is patterned closely after the 

. 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 

 ‹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. 

 ‹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 

 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 

 monograph, but the NDA and ANDA are still reviewed by the agency and even though there is no requirement in 

 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.  

 ‹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. 

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 

 ‹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, 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."  

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, 

 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 

. "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." 

 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 

 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 

 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."  

 ‹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.  

 Key to understanding the limits for Class 2 solvents is understanding that they were calculated using what ICH and 

 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 

 ‹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 

 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 

 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."  

 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." 

 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." 

 ‹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), 

 ‹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." 

 ‹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. 

 ‹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, 

 ‹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>."  

"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. 

 Some over-the-counter (OTC) products also may fall under the 

 ‹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 

 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. 

 monographs fall under the requirements in 

 ‹467›. Other OTCs may be approved under an NDA or ANDA but do not have a 

 monograph. "In these cases, we will probably continue to apply the ICH Q3C guideline," says Ouderkirk.  

Engel and other OTC analysts largely support the 

 ‹467› changes. "I think they are good rules. The fact that 

 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." 

 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 

 revision comes out is that there is always a group of products that have been tested according to an older version of 

 and then if they don't immediately employ their (raw) material in the manufacture and it sits in a warehouse while the 

 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 

 monograph, uses it in manufacture and then 

 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 

 changes, then they simply can't use that material in manufacturing because the company must test according to the 

 that is in effect when manufacture begins and must retest. 

 ‹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.   

notice that would clarify when compliance with the 

 ‹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 

 ‹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. 

Articles

USP 467 Residual Solvents will take effect on July 1, 2008. But does the industry understand these specifications-and is it prepared?

Clearing the Air on Residual Solvents

The Parenteral Drug Association recently held its first global conference on emerging manufacturing technologies. Among the  presentations were those discussing the latest in disposable technologies, aseptic filling and closing, and barrier systems. Clearly, technology vendors have stepped up efforts to streamline processes and better handle complex drug products. 

Whether manufacturers are ready to implement these technologies, however, wasn't so obvious. During a luncheon, my tablemates debated over whether drug makers will ever be able to provide personalized medicine. In the end, they generally agreed this was a long way from fruition. But the conversation prompted a PDA official to pose an even tougher question: Faced with two compounds, one that is simple, easy to manufacture, but must be administered monthly, and another that is much more complex but can be taken only once a year, which would you pursue to market?  

What was so surprising was that, unlike the personalized-medicines issue, no one offered an immediate and definitive opinion. After a seemingly long silence,    the pros and cons were weighed: How long would the simpler formulation sustain a reasonable market share before a competitive product was marketed that required less frequent dosing? Would the inconvenience of more frequent dosing have a higher risk for patient noncompliance? The complex formulation would cost more and carry a higher risk of error during development, but it offered a preferred dosage regimen and patient compliance would (theoretically) be greater.  

The general consensus was that, all points considered, manufacturers could not afford 

 to pursue the once-per-year dose. Patient-focused healthcare is here and now, ready or not. Sooner rather than later, technologies will have to be updated, not only, as one speaker stated, because "the aggressive use of technology makes good business sense," but also because it will soon be common sense.  

The Parenteral Drug Association recently held its first global conference on emerging manufacturing technologies. Among the presentations were those discussing the latest in disposable technologies, aseptic filling and closing, and barrier systems. Clearly, technology vendors have stepped up efforts to streamline processes and better handle complex drug products.

Pursuits of Business

Like all consumers, patients and healthcare providers want products that will make their lives easier, and any product that makes administering or taking an injection easier is bound to be popular. It's no wonder, then, that the vast majority of pharmaceutical companies are noting the advantages of prefilled syringes and scrambling to include them in their portfolios. 

Prefilled syringes are not a new technology by any means. They debuted during World War II to accommodate the need for on-the-spot, sterile medications in battlefield hospitals. The next big push into the market came when Becton Dickinson and Company  (BD, Franklin Lakes, NJ) began supplying glass prefillable syringes to support Dr. Jonas Salks' poliomyelitis vaccination program in the early 1950s. Prefilled syringes continued to be used mostly for delivering insulin or human growth hormone. In the past five years, however, they have really come into their own,  becoming not just a desirable product but almost a required product for parenteral makers to offer. 

"If you're going to launch a new product with an already competitive indication, it should be filled in a prefilled syringe for success on the market," says Jörg Zimmermann, head of production at Vetter Pharma-Fertigung GmbH & Co.  "Most innovative new products, if they're liquid, are going to be in a syringe, when appropriate." 

The numbers attest to this: a study conducted by BD and IMS Health shows that the market for prefilled syringes is expected to grow by 12.8% per year. In 2006, about 1.4 billion prefilled syringes were sold, and by 2010 the quantity is expected to top 2.4 billion. 

The sudden and intense interest in prefilled syringes can be attributed to several changes in the industry.  

 The market has seen an increase in the number of biotechnology therapies and drug candidates that can only be administered by injection. These new treatments target a wide range of areas such as multiple sclerosis, fertility, osteoperosis, hepatitis, rheumatoid arthritis, cancer, anemia, and hemophilia. 

Some biotech-based drugs require frequent injections to be administered by the patients themselves, and it's these patients, according to Michael N. Eakins, principal consultant with Eakins & Associates (West Windsor, NJ), who stand to benefit the most from the ease of use a prefilled syringe offers. 

"A prefilled syringe takes out a series of operations, which makes it quicker and easier," notes Eakins. "It's a great advantage from the patient point of view in ease, safety, and training to have a dose all ready to go in a prefilled syringe." 

It's patients who are the true driving force behind the demand for prefilled syringes. Measuring out a dose from a vial into a syringe may be time-consuming and pose a risk for error for those with little training. Moreover, diseases such as rheumatoid arthritis often make it difficult or even impossible for patients to hold a vial and withdraw an accurate dose. Pharmaceutical products that started out as a lyophilized formulations have been changed to liquid formulations to be packaged in prefilled syringes. Berlex's (Wayne, NJ) "Betaseron" multiple sclerosis treatment, and the human growth hormones "Norditropin" (Novo Nordisk, Princeton, NJ), and "Nutropin" (Genentech, San Francisco, CA) all have been reformulated from lyophilized to liquid and are now offered in prefilled syringes. 

 Syringe component suppliers have stepped up to meet  the rising demand in ready-to-use units. Stelmi's (Paris, France) ready-to-use plungers and BD's "Hypak SCF" prefillable syringes eliminate the need for washing, depyrogenation, and sterilization at the filling site. Ready-to-use components are washed, EtO or gamma sterilized, and validated for direct use. 

 One of the greatest benefits is the significant reduction in the amount of product needed to overfill the container. "By using a prefilled syringe, 10, 15, sometimes even 20% of the API can be saved," Zimmerman notes. "With this all-in-one solution, there is no substance loss through refilling. We've had customers that converted from vial to prefilled syringe that were able to scale down their API process because they didn't need as much," Zimmerman continues.  

Overfill for a prefilled syringe is significantly less—in the single digits, according to Cory Lewis, director of new business development with Baxter BioPharma Solutions (Bloomington, IN). "When you're talking about bulk drug API that's in the thousands of dollars per gram, there is a true economic savings that companies can yield," he says. A BD study indicated a potential for up to 23% more product dose yield in a prefill compared with a vial, as less product is lost in the transfer from a vial to a syringe.  

 Although plastic prefilled syringes are gaining in popularity in Europe, glass barrels are still preferred in the United States: 99% of the prefillable syringes sold in the US by BD are its Hypak prefillable glass syringe. Glass is heavily favored, primarily because it has been part of the industry for a long period of time.  

"The real problem with the plastic is that it is less well known and less well characterized. Glass has been around as a container for drugs since the Egyptian empire," Michael Eakins points out.  

Glass prefilled syringes are made of Type I borosilicate glass, the same type that has been used for vials for a long time. The downside to using glass, however, also is well known: Glass contains alkali ions, which can lead to a surface reaction that forms a small amount of sodium hydroxide. After years of observing this effect in glass vials, most pharma companies know what to expect and have devised ways to get around the problem.  

Until recently, plastics were not as clear as glass, making it difficult for companies to visually inspect their products for particulates. But recently, more companies have taken an interest in plastics, mainly owing to recent advances in their design and makeup. Original plastic syringes, which were introduced in the early 1990s, were made from polypropylene. Several companies now offer syringe barrels made of cyclic olefin polymer or cyclic olefin copolymer, which is as clear as glass but less heavy and less likely to break. Cyclic olefin plastics also are more resistant than polypropylene to water transmission, which may help lengthen the shelf life of the drug product. 

BD, West Pharmaceuticals, and Baxter BioPharma are all developing plastics for prefillable syringes. In 2000, BD launched a plastic prefillable syringe system known as "BD Sterifill SCF," which is transparent, resistant to breakage, and lightweight. Sterifill is composed of BD's "Crystal Clear Polymer," an amorphous, high-performance polycycloolefin. The company also has released its "BD Uniject" single-use, auto-disable prefill injection device, which contains a small, blister reservoir filled with the drug attached to the needle. Squeezing the reservoir releases the drug. 

West's Resin Crystal Zenith (CZ) silicone-free syringe system is made of cyclic polyolefin and has high heat resistance and low temperature characteristics. It is also break-resistant and clear. 

Awaiting approval is Baxter's most recent development, "Clearshot," which, like Sterifill and CZ, is break resistant, lightweight, and offers high clarity. The process used to produce Clearshot is somewhat unique: the syringe is formed, processed, and sterilized inline. "We start off with a resin pellet and at the end of the line comes a syringe with the drug product, stoppered," says Cory Lewis. 

Plastics have a ways to go before they're widely accepted in the pharmaceutical industry, but as more companies produce purer, more glass-like plastics, plastic syringes begin to gain ground. "There has been much more interest in plastics," notes Eakins. "It's quite clear the interest is increasing." 

Vetter produces a dual-chamber syringe in which one chamber is filled with lyophilized product and the other is filled with diluent. When the plunger is pressed, the diluent and lyo products mix and can then be injected. The dual-chamber syringe can also be used with powder and liquid or two liquid products. The latter is, as Vetter's Zimmerman says, a niche market, but it can be used for a multi-dose application that requires a preservative but might not be compatible with the protein for storage.  

 A necessary component of the prefilled syringes is the rubber stopper or plunger, which carries with it its own challenges. Because stoppers are in prolonged contact with the drug, the primary concern is with leachables from the rubber interacting with the drug.  

One example is the case of the antianemic "Eprex." Produced by a subsidiary of Johnson & Johnson (New Brunswick, NJ), Eprex was reformulated to eliminate human serum albumin for the European market and then packaged in a prefilled syringe that replaced the uncoated stopper that had been used before with a coated one. The new formulation of the drug interacted with leachables from the stopper and was later linked to pure red cell aphasia (PRCA) in certain patients, leading to severe anemia.  

To combat the problems that may arise from interactions between drugs and rubber stoppers, Stelmi has developed high-purity formulations with a low level of extractables for their rubber components. In the late 1990s, Stelmi launched its "UltraPure 6901" formulation adapted to prolonged contact with water for injection. In 2004, as prefilled syringes continued to gain in popularity, the company began producing elastomer-based formulations 6955 from a new elastomer known as BIMS, which is exempt from oligomers and, thus, less prone to leaching into the drug.  

Meanwhile, West Pharmaceutical Services (Lionville, PA) is taking a different tack. Rather than retooling the rubber formulation, the company has begun molding a laminate known as "FluroTec" film onto its stoppers. The film acts as a barrier between the stopper and the drug, reducing the amount of leachables going from the rubber stopper to the drug in the syringe. 

Concern over extractables and leachables is growing. At a recent AAPS conference, extractables and leachables came third in a list of the Ten Hot Topics of 2007, whereas a mere seven years ago, they didn't even make the list. Whether made of glass or plastic, prefilled syringes deserve special attention when it comes to controlling extractables and leachables.  

When it began moving one of its protein drugs to a prefilled syringe, Amgen, Inc. (Thousand Oaks, CA) was surprised to notice that the protein was aggregating. After much investigation (and cooperation between Amgen and BD, the manufacturer and supplier of the syringes), the culprit was found to be tungsten, which is used to hold open the fluid channel at the base of the syringe during the manufacture of the glass. The heat used during the molding process vaporized some of the tungsten, which then settled in the glass at the base of the needle. Prolonged exposure of the drug to the tungsten resulted in visible particles in the solution. BD now has the ability to produce a tungsten-free prefilled syringe. 

Some drug makers are concerned that plastics pose a greater risk of extractables and leachables. Plastics and resins are composed of many different components and the formulations can easily change, so there is more uncertainty and potential for extractables. When working with plastics, "you have to take more chemicals into consideration, and therefore there are more unknowns because the plastic vendors will not tell you ... the exact formulation because it is proprietary," says Eakins. The uncertainty means that more testing is often necessary when packaging in plastics, and, according to Eakins, "the last thing you want to do is a lot of research on your packaging, it makes the risks even higher."  

One method of cutting down on the amount of testing is to improve communication between pharmaceutical manufacturers and the companies supplying them with prefilled syringe components. Most components manufacturers will provide their clients with lists of possible extractables and leachables, thus allowing the pharmaceutical manufacturers to narrow the field when testing their drugs. Robert Swift, principal engineer of Amgen, hopes that the increased communication between suppliers and the biopharmaceutical industry will "allow [pharma] companies to identify and mitigate formulation-container interactions very early in development." 

Silicone, however, is one ingredient that's proving very difficult to eliminate. Silicone is used to coat the inside of syringe barrels. Although silicone poses no threat to some drugs, others have exhibited adverse reactions caused by prolonged exposure to it. West Pharmaceutical Services will soon be introducing its resin CZ system, which eliminates the need for silicone. The plunger is coated with FluroTec, which protects the drug from leachables from the rubber and provides the lubrication needed to allow the plunger to move. Other companies are baking on the silicone, and still others are working to reduce the amount of silicone in the barrels to the least amount possible to still allow the plunger to move.  

Besides testing for leachables, pharma companies also must test for break-loose and gliding forces for drugs of various viscosities. For those forces to remain low, there must be some sort of lubricant present. Thus, eliminating or reducing the amount of silicone is challenging. 

Figure 1: Glass syringes are currently preferred, and innovations in automation and robotics have increased the efficiency and consistency of handling glass prefilled syringes on the processing line. The photo shows automated heat-tunnel unloading of prefilled syringes (courtesy of Vetter Pharma-Fertigung GmbH & Co. KG).			

Increasing interest in prefilled syringes has lead to innovative solutions in filling and stoppering technologies, barrier designs, automated processing and transfer systems, and robotic handling.  

 Filling and stoppering syringes present a unique set of challenges than those encountered when processing vials.  

"The method you choose to fill and stopper a syringe can influence the stability of the drug product, the movement of the product inside the syringe during shipping, and, in some cases, the sterility assurance of the product," says Shawn Kinney, president at Hyaluron Contract Manufacturing (HCM, Burlington, MA).

Vacuum stoppering technology has been available for several years, but vacuum filling is relatively new. Vacuum stoppering has, until recently, only been performed offline, away from the fill line in a vacuum box. Recently, syringe manufacturers have developed vacuum filling and stoppering capabilities online, primarily for viscous products.  

Pulling a vacuum through very thin solutions such as water for injection or buffered solutions causes the liquid to boil and splatter. If splattering occurs during the stoppering process, the liquid product may be entrapped in the ribs of the stopper, posing a potential sterility issue.  

Successfully removing air from thin solutions does have several advantages, including increased product stability, lack of stopper movement during shipment and post-sterilization processing, and even potentially enhanced sterility assurance of the solution. Hyaluron has patented a bubble-free filling process that eliminates the air inside the syringe. Bubble-free filling is especially beneficial for oxygen-sensitive pharmaceuticals and proteins that are sensitive to a gas-liquid interphase that appears on small gas bubbles inside the syringe.  

"Some proteins tend to rearrange themselves such that the hydrophobic groups point up into the gas phase and the hydrophilic amino acids point down into the liquid phase, which causes more rapid degradation, says Kinney. "The presence of a gas bubble, in conjunction with the silicone coating, will further exacerbate protein aggregation."  

Other companies are reportedly working on closed-filling systems similar to those used for vials (1).

 The challenges in handling the shape and composition of syringes also are leading to new barrier system designs, specifically isolators and restricted access barrier systems (RABS). 

"Traditional cleanrooms are being phased out in exchange for operations within RABS or isolators," says Eric A. Isberg, product manager, Pharmaceutical Operations, Robert Bosch Packaging Technology (Brooklyn Park, MN).  

Whereas vials can easily sit on a track and be directed along their sides with relatively simple belts and conveyors, syringes require direct handling (see Figure 2). Syringes are unstable because of their high center of gravity and therefore require specialized transport systems to reduce the risk of breaking or scratching. The finger flange of the syringe can be the most vulnerable, so the handling system must allow space between each unit.  

Figure 2: Automated filling lines provide the necessary direct and individual handling of syringes (photo courtesy of Baxter BioPharma Solutions).			

 Syringes can be transported using pucks constructed of thermoresistant plastic or stainless steel. The pucks hold the syringes upright as they move them through heat tunnels. Specially designed trays transport the syringes into autoclaves. Traditional lines are designed to hold syringes by the flange, but some experts believe this system poses a risk to breakage.  

"We are seeing more systems that have either pucks or systems that hold the syringe throughout the transport systems using vacuums on the starwheel. This allows the syringes to be elevated as needed without being supported on the bottom or by the finger flange" says Isberg. 

Many companies are coming up with innovative materials and manufacturing methods to feed the growing demand for prefilled syringes.

Big Shot: Developments in Prefilled Syringes

Even at minute quantities, unwanted chemicals present in pharmaceutical ingredients may greatly influence a drug product's efficacy and safety. While researchers strive to eliminate or control impurities, they rely on fast analytical tools with high sensitivity and specificity to better detect, identify, quantitate, and characterize impurities. The technology for impurity analysis has improved beyond the traditional chromatographic (

 high-performance liquid chromatography [HPLC] and gas chromatography [GC] for volatile impurities) and spectroscopic methods (

 GC–mass spectrometry [GC–MS]). Scientists are gaining an ever-clearer picture of their materials' constituents. In some cases, technology is revealing never-before-seen impurities even in compounds thought to be well understood. 

Along with improving analytical tools comes a growing concern about genotoxins—molecules that may bind or break DNA even in parts-per-million concentrations—which are only now practical to monitor.

Better information about pharmaceutical impurities is generating new questions. What is the best way to handle them? How should we report them? How do they really affect overall product quality? How should control procedures be put in place? Ingredient suppliers are working—and debating—with regulatory agencies to develop guidelines designed to eliminate redundant testing for APIs, explain the composition of excipients, and reasonably control the genotoxic impurities in both.  

 LC and GC techniques with conventional detectors have been the traditional analytical methods for identifying and quantitating nongenotoxic impurities. According to a 2003 survey, HPLC accounted for approximately 53% of the reported analytical separations used in 1999–2001 (1). In these applications, specificity, sensitivity, and matrix interference remain the primary analytical challenges (2). These techniques may not necessarily measure impurity levels accurately. They assume that impurities are structurally related to the drug substance, and therefore have similar detector responses; this is not always the case.  

Hyphenated techniques, including LC–MS, GC–MS (accounting for 8% and 2%, respectively, of the methods used in 1999–2001), and chromatography tandem mass-spectrometry (LC–MS–MS) are more sensitive and can provide better separation (see Figure 1) (1). In addition, MS–MS yields more accurate information about the structure of impurities. 

Figure 1: Scientists are increasingly relying on hyphenated and tandem techniques to analyze their compounds, thereby enabling them to better detect and identify impurities (Waters Quattro Micro LCâMSâMS instrument with Waters Alliance 2695 HPLC). 			

				"Incorporating this information with those obtained from NMR and IR techniques, one can identify the impurity with a fairly good degree of accuracy," says Liakatali Bodalbhai, group leader, Analytical Sciences R&D, DPT Laboratories (San Antonio, TX). "However, only by synthesizing the possible molecule and comparing its fragmentation pattern in MS and retention time by HPLC to the impurity of interest can one conclusively identify that impurity." 			

Bodalbhai points out that the development of multiple ionization modes in LC–MS and LC–MS–MS, namely electrospray ionization, atmospheric pressure chemical ionization, and atmospheric pressure photoionization, has expanded the capabilities of these techniques for a large class of compounds. Newer technologies include fast chromatography data treatment such as signal averaging, new LC–NMR platforms, thermogravimetric–MS for volatile impurities, and LC–MS–NMR (3).  

"Incorporating NMR to LC–MS would make this technique one of the most powerful tools for an analytical chemist," says Bodalbhai. With this technology, scientists can fragment a molecule and obtain structural information as well as map atom-to-atom connectivity of the molecule, thereby generating three-dimensional structures of the isomers.  

"On-line implementation of techniques is gaining popularity and the ability to conduct identification, characterization, and quantitative analysis  at the same time will be one of the trends of the industry," predicts Qingxi Wang, director of Global Pharmaceutical Globalization, Merck Co., Inc. (Whitehouse Station, NJ). "For example, interfaced LC–MS–NMR could potentially be a widely used technique for the characterization of organic impurities." 

Wet chemistry is currently the compendial method for inorganic impurity analysis. However, ICP–AES and ICP–MS are widely used and potentially methods of choice because of their higher sensitivity and selectivity. Other techniques for detection and characterization of inorganic impurities include laser induced bombardment spectroscopy, scanning electron microscopy-energy dispersive X-ray, and X-ray fluorescence (3). 

 In general, impurities should be quantitated at levels ≥0.03 or 0.05% by weight according to ICH guidelines (see Table I). Genotoxic impurities or potential genotoxic impurities must be controlled at levels significantly lower than the 0.03–0.05% levels that are typically reported by an HPLC impurity assay. Typically, developing limit tests (

 <50 ppm) for highly toxic impurities is readily achievable, however it can be difficult to develop a test to control a particular genotoxic impurity at 1 ppm (0.0001% w/w). 

	Table I: ICH Q3A (R2) thresholds for impurities in drug substances.			

"There is a huge difference between the two," says Sandeep Modi, director of Quality Management at Bristol-Myers Squibb (New Brunswick, NJ). "For genotoxic impurities we need very sensitive and selective methods. One needs higher sensitivity to determine ppm-level impurities and selective methods to separate low levels of genotoxic impurities from base line noise and other organic impurities. The typical HPLC methods with a nonspecific detector (

 UV) that are used to measure organic impurities may not be appropriate to quantitate low ppm levels of genotoxic impurities." 

The quantitation of low levels (in the range of ppms) of impurities is the challenging part, notes Modi, and using specific detectors such as MS or MS–MS with LC will significantly improve the method selectivity and the quantitation limit. The goal for scientists is to identify potential genotoxic impurities early in development, develop analytical methods to test for these impurities in the intermediates, and if possible, to demonstrate that the manufacturing process controls them before reaching the final drug substance.  

"If you eliminate them early enough, then your actual active drug substance is pure, free of genotoxic impurities," says Modi. 

Improvements in analytics as well as those in synthetic chemistry also have led to a greater number of synthetic routes discovered. Molecule synthesis has improved with better reagents, better techniques, better reaction types, and better control. As a result, some APIs now have as many as five possible synthetic routes. And APIs produced according to those synthetic routes may have different impurity profiles.  

 monograph lists the minimum set of impurity tests that must be conducted. Currently, a company making an API must comply with all the tests listed in the published 

 monograph, even if the company uses a synthetic route that is different from the original and therefore has an impurity profile that may or may not contain all the impurities listed in the monograph. Even if the company knows for certain (either because of the route of synthesis or some other scientifically justifiable means) that some monograph impurities will not be present, it must still test for every substance on the list. In addition, the company would still have to test for any other impurities that might be in its compound.  

Flexible monographs were designed to eliminate redundant testing. They allow scientists to conduct only those tests that are relevant to their compound. If a company's API has an impurity profile that is different than the original, the company could conduct a full scientific evaluation of the material and file information with USP. Moreover, the company must notify FDA upfront that it plans to submit a different impurity profile, including the limits on each impurity as part of its drug application. The monograph would become effective upon FDA approval of the product.  

Not surprisingly, generics companies stand to benefit from the flexible monographs program. Still, these companies face technical challenges in qualifying impurities (see sidebar, "Qualification of impurities in ANDAs"). 

				"GPhA has not put out a unified public statement or position on flexible monographs," says Gordon Johnson, vice-president regulatory affairs for Generic Pharmaceutical Association (Arlington, VA). "However, we have been supportive of this effort in a number of stakeholder meetings with USP." 			

While API scientists aim to eliminate or control impurities, excipient makers are trying to move away from the impurity mindset and instead are advocating a better understanding of excipient composition and components, especially if these components are essential to some performance of the material or the drug product.  

"Right now, there is a gross misunderstanding of this issue. Excipients come from a lot of different areas. They are from sources that are not synthetic chemistry, and by design they are not supposed to be pure. They are not in a drug product to be pure, they are there to be functional," says Dave Schoneker, director, Global Regulatory Affairs, Colorcon (West Point, PA) and Chair-Elect of the International Pharmaceutical Excipients Council of the Americas (IPEC Americas). 

Sometimes the overall performance can be attributed to the presence of a minor component (

). "So 'pure' excipients are not necessarily good excipients, depending on performance," says Schoneker.  

For example, microcrystalline cellulose contains several components, including pulp residues, sugar residues from the hydrolysis, and hemicelluloses. When too much of these "impurities" are removed, it can compromise performance of the excipient. Determining how much is too much, though, is not an easy task.  

"It's a bit complicated because we don't have the analytical methods and understanding that we really need to be able to say 'These are the definitive limits for this component,'" says Chris Moreton, vice-president of Pharmaceutical Sciences at Idenix (Cambridge, MA). The only limitation, for safety reasons, is on toxic components, especially for parenteral preparations such as parenteral grade dextrose, mannitol, or povidone that also have restrictions on endotoxins.  

"We don't have a good enough understanding of any excipient to be able to say, 'This is the item that needs to be controlled and it will be the same for every formulation,'" says Moreton. 

"The big issue is the overall compositional profile and understanding how that relates to the use of the excipient," says Schoneker. "Users sometimes ask for an impurity profile when they should be asking for composition." This understanding is especially critical when users contemplate switching suppliers. Although both materials may meet all specifications, they may have different concomitant components, and so their performance during actual processing may differ. 

Obtaining a useful compositional profile will again put the focus on good analytical methods.  

"Some of the hyphenated techniques such as LC–MS may be able to reveal components that were never seen before. And if we are ever able to get a good solvent that will dissolve celluloses easily, we might be able to get more information. In order to go deeper into the composition of excipients we're going to need better applications or new analytical techniques to understand what we are doing," says Moreton. 

Even if these techniques were available, the data generated might not be meaningful. "I would want to see data going over several years to see what the inherent variability of those components were in relation to time of year, harvest, and so forth. Without that, just introducing the technique is not going to help. In fact, it's going to make things worse." 

Collaborating with the Japanese and European branches of TriPEC, IPEC-Americas is working on a composition guideline to help excipient suppliers communicate the overall composition of their products and why the components are present while retaining confidential proprietary information.  

"We are trying to initiate a better dialogue between makers and users so that users understand what it is they are working with, using good science to determine how materials should be described," says Schoneker.  

The IPEC guideline is the first step. Afterward, the biggest challenge will be getting excipient users to think of excipients in the correct framework.  

"We want to educate the industry that they cannot think in traditional API terminology when they are dealing with excipients," says Moreton. "They simply don't work the same way." 

A major change in impurity testing involves a new regulatory guidance designed to tightly limit substances possessing potential for genotoxicity. The European Agency for the Evaluation of Medicinal Products (EMEA) guidance on genotoxic impurities, which became effective on Jan. 1, 2007, now applies a 1.5 μg daily exposure limit for such substances in most pharmaceuticals based on a precedent application of the threshold of toxicological concern (TTC) concept to food additives and food contact materials. Before the EMEA draft guidance, genotoxic impurities had been addressed only as a footnote in ICH Q3A (R2) "Impurities in New Drug Substances" (see Table I).  

In 2004, the Pharmaceutical Research and Manufacturers of America (PhRMA) formed a task force to discuss genotoxic impurity limits. Concerned the 1.5 μg/day limit would be applied to drugs synthesized in the United States, even while these drugs were still in clinical development, the PhRMA group proposed a staged TTC approach that ties permissible impurity levels to the stage of development (see Table II) (4). Because clinical studies are conducted with limited duration of dosing, the group reasoned that total exposure is very low, and thus higher intake levels should be allowable during early clinical studies without a net increase in risk. PhRMA's staged TTC approach applies to all clinical routes and to compounds at all stages of development, for identified and predicted impurities. The TTC limits would not apply to already marketed products. 

	Table II: Staged TTC approach proposed by PhRMA.			

				Some questions surrounding both the EMEA and PhRMA positions could be heard, however, at last fall's annual meeting of the American Association of Pharmaceutical Scientists (AAPS). 			

"There's certainly a need to draw the line somewhere, but in my view it's gone overboard. It would appear that both the regulators and industry have become so focused on positions, that the bigger question of whether the new work processes created are actually benefiting the pharmaceutical consumer is being overlooked," commented one industry scientist (name withheld by request) . 

Others point out that the original TTC design purposefully excluded consideration of the impact of the human body's natural DNA repair system, and the fact that the underpinning scientific studies were conducted in rodents, which have DNA repair systems that are about 10-fold less effective than those in humans. "There is an approximate two to three orders of magnitude of extra conservatism built into the original TTC limit that for some reason didn't seem to get much attention in translating the concept to pharmaceutical usage," another industry scientist points out. 

Meanwhile, the industry is waiting for the release of an FDA draft guidance on genotoxic impurities, which should clarify the issue.  

"Right now (the draft guidance) is going through some internal editing and clearing through various levels of CDER. It is still in draft form and hopefully in the not too distant future we will get it out for comment," said Tim McGovern, supervisory pharmacologist, Division of Pulmonary and Allergy products at FDA.  

In preparing to issue its own draft guidance, FDA experts have studied both the EMEA and PhRMA proposal for limits on genotoxic impurities. "We've taken a look at both of those. In various meetings where we've presented on the issue, we've said that 1.5 μg/day appears to be a good threshold limit. We also thought that a staged approach, especially during clinical development, was a reasonable approach to take. So our plan right now is to incorporate a staged TTC approach into the document," says McGovern.  

"We've dealt with issues regarding genotoxic impurities for a number of years. It got to a point where the issue was coming up on a regular-enough basis that we thought a guidance document would be helpful," says McGovern. "We would have developed a guidance regardless of whether EMEA had or not." 

As technology for impurity analysis improves, scientists are gaining better information and asking for more regulatory guidance.

The Impact of Impurity Analysis on Future Regulations

 (Greenville, NC) have developed an extended-release drug delivery platform for tablets requiring zero-order or near-zero–order 

	According to Metrics's development scientist Brian Woodall, the delivery system is based on a unique ratio of FDA-approved, 

-grade excipients as well as a minor thin-film coating (3–5%). The technology, currently the subject of a provisional patent application, is similar to a matrix tablet system in that it depends on the behavior of the selected polymers to swell, dissolve, and form a gel-like mass at a specific rate, which enables a controlled and steady release. The film coating prevents initial dose-dumping when the tablet is dropped into a dissolution vessel, thereby extending the release rate. The manufacture of the system involves dry-blending the active ingredient, compressing the tablet, and applying the film coating.

	Woodall and co-developer Brad Gold, Metrics's director of pharmaceutical development and new technologies, report the delivery mechanism is pH-independent, suitable for both low and relatively high-dose active ingredients, as well as for water-soluble and -insoluble compounds that are hydrophobic or hydrophilic. The company plans to present more information about the technology at the American Association of Pharmaceutical Scientists annual meeting in November.

Metrics Files Patent for Controlled-Release System

The findings of PTE/PT's survey of employment-related issues in the European and US pharmaceutical industries.