Beginning this month, we are featuring monthly reader polls to gain your feedback on key advances in the pharmaceutical sciences and manufacturing. As the scientists and technical experts on the front lines, your input is a crucial component in understanding what the industry has achieved and where it will go in the future. We encourage you to provide your feedback in our first poll, which is examining advances in oral drug delivery and oral product forms. We will share the results with you at PharmTech.com, and along with further analysis, our July issue will take a retrospective and prospective look at drug substance and finished drug-product manufacturing, formulation development and drug delivery, outsourcing, and analytical testing.

We are interested in your feedback as well. In addition to our reader polls, we invite you to provide your input on what you think have been major achievements in drug substance and finished drug-product manufacturing, formulation development and drug delivery, outsourcing, and analytical testing. Lend your expertise and offer your input in the comment section to this blog or email your input to Patricia Van Arnum, executive editor, pvanarnum@advanstar.com. We look forward to hearing from you.

Topical formulations can be used to treat local and systematic indications, offer ease of delivery, facilitate patient compliance, and avoid the problem of first-pass metabolism. Successfully developing a topical formulation requires an understanding of the physiochemical properties, such as release characteristics, composition of the drug-delivery system, and the nature of the drug-delivery vehicle. Manufacturing a semisolid dosage requires implementing a CMC (chemistry, manufacturing, and controls) strategy to ensure stability, photosafety, avoidance of product degradation, and minimization of process impurities. The Pharmaceutical Technology webcast, “Optimizing Topical Drug Formulation and Manufacturing,” provides insight on recent advances in topical drug formulations, the latest regulatory/pharmacopoeial requirements in product quality and product performance, and strategies to optimize manufacturing for topical drug products.

Speakers include: Vinod Shah, PhD, chair of the Special Interest Group, Regulatory Science of the International Pharmaceutical Federation and distinguished pharmaceutical scientist and consultant to the US Pharmacopeia; Majella Lane, PhD, senior lecturer in pharmaceutics at the School of Pharmacy at the University of London; and Michael Lowenborg, R&D manager of formulation and process development at  DPT Laboratories.

Additional information and registration for the webcast may be found here.

Topical formulations can be used to treat local and systematic indications, offer ease of delivery, facilitate patient compliance, and avoid the problem of first-pass metabolism. Successfully developing a topical formulation requires an understanding of the physiochemical properties, such as release characteristics, composition of the drug-delivery system, and the nature of the drug-delivery vehicle. Manufacturing a semisolid dosage requires implementing a CMC (chemistry, manufacturing, and controls) strategy to ensure stability, photosafety, avoidance of product degradation, and minimization of process impurities. The Pharmaceutical Technology webcast, “Optimizing Topical Drug Formulation and Manufacturing,” provides insight on recent advances in topical drug formulations, the latest regulatory/pharmacopoeial requirements in product quality and product performance, and strategies to optimize manufacturing for topical drug products.

Speakers include: Vinod Shah, PhD, chair of the Special Interest Group, Regulatory Science of the International Pharmaceutical Federation and distinguished pharmaceutical scientist and consultant to the US Pharmacopeia; Majella Lane, PhD, senior lecturer in pharmaceutics at the School of Pharmacy at the University of London; and Michael Lowenborg, R&D manager of formulation and process development at  DPT Laboratories.

Additional information and registration for the webcast may be found here.

In hot-melt extrusion, an amorphous solid solution of the crystalline drug substance is formed under shear and heat. Solubility parameters, combined with other physiochemical characteristics of the drug and excipients, can by used as predictive indicators in selecting initial formulation components. Successfully implementing pharmaceutical hot-melt extrusion dosage product development, however, requires not only careful selection of the active and inactive ingredients, but also of the appropriate processing conditions. Inadequate processing conditions can lead to thermal degradation of polymers, drug, or other formulation components. Melt-extrusion processing temperature, screw speeds, feed rates, and screw design play a crucial role in implementing the technology.

Producing a desired dosage form requires the optimization of both the formulation-development and manufacturing processes. The upcoming webcast, “Pharmaceutical Melt Extrusion Process Development,” examines how initial process parameters can be selected and optimized for a product produced using hot-melt extrusion. The webcast includes speakers from Roche, American Leistritiz, and Evonik, and will be broadcast on Oct. 4. Details may be found here at the PharmTech website.

Reference

1. P. Van Arnum, “Solubilizing the Insoluble,” Pharm. Technol. 34 (11), 50–56 (2011).

Understanding critical quality attributes will help Pfizer develop robust design spaces and, ultimately, achieve real-time release, said Gerry Migliaccio, senior vice-president of network performance for Pfizer Global Supply, according to In-Pharma Technologist. Migliaccio made his remarks at a meeting of FDA’s Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. Using QbD as a basis, and process analytical technology to establish manufacturing controls, Pfizer believes it will be able to reduce quality-control costs, achieve real-time release, and quickly get a return on its investment.

But not all companies are rushing to adopt QbD. Manufacturers of small-molecule generic drugs fear that spending the extra initial time and effort to adopt QbD could prevent them from being the first to file an application for their products. “If you’re not first to file, you may as well be last,” said Yatindra Joshi, vice-president of generics R&D for Teva, at the same FDA meeting. Consequently, some generic-drug manufacturers aren’t willing to gamble that the benefits of QbD will outweigh the profits lost by not being first to file.

If Pfizer and other heavyweights adopt QbD, it could boost patients’ confidence in the safety and efficacy of marketed drugs. But patients would benefit even more if generic-drug manufacturers felt freer to pursue this initiative. By making some elements of QbD mandatory in filings, FDA could “level the playing field,” said Joshi. This idea seems like one plausible solution that could be of advantage to the industry and consumers alike.

For FDA’s evaluation of the QbD program so far, please watch for Pharmaceutical Technology’s September issue, in which CDER’s Helen Winkle and Moheb Nasr analyze the initiative’s present and future.

The weight of children, and all individuals for that matter, varies within certain age ranges. Drugs are formulated based on age and weight, so it makes sense that dosing instructions address both. A major concern regarding dosing labels for children, in particular, is that if a child falls into a certain age range but weighs less than average for that age range, then that child could be overdosed when given a dose based on age alone.

According to the FDA briefing materials, “It has been reported that seventy percent of emergency department visits, across all age groups, related to single ingredient acetaminophen were due to unintentional overdose and two-thirds of those overdoses occurred in children less than 12 years of age.” In addition to unclear labels and labeling, causes of overdosing include: “general knowledge deficits, varying dosing devices, varying formulations and concentrations… and inadequate provision of dosing instructions to patients by their providers.”

Currently, the under-age-2 labels for OTC medications containing acetaminophen say, “Consult a doctor.” Labeling instructions for children under 6 months of age may retain the “Consult a doctor” statement, but weights and ages should be provided for children 6 months to 24 months, according to the committee recommendations.

The official minutes of the joint advisory committee meeting should be published in the Federal Register in the coming days and will contain additional details. Briefing materials used for the meeting were provided by officials within FDA, the Consumer Healthcare Products Association, and McNeil Consumer Healthcare; they are available online. The committees reviewed available pharmacokinetic, efficacy, and safety information as well.

FDA is not required to accept the committees’ recommendations but typically does.

One of the paper’s authors, Dr. Richard Weisler of UNC states in the release that “To put this in perspective, the number of 2007 U.S. unintentional drug poisoning deaths alone represents tragically about 4.6 times as many deaths as all U.S. fatalities in both Operation Iraqi Freedom and Operation Enduring Freedom in Afghanistan from the beginning of both wars through Feb 20, 2011.”

FDA’s response to the problem has been a series of educational initiatives for patients and physicians. Drug makers have responded by developing innovative formulations to discourage abuse of prescription opiates. This type of formulation work runs counter to the type of strategies that usually concern drug makers: generally, the idea is to get the drug to its target at high concentrations as fast as possible for as long as possible. In the case of opiates, they are tasked with getting the drug to target at therapeutic concentrations, but making it impossible to reach concentrations that are too high or reach them too quickly.
This week, Pain Therapeutics Inc. released results from its Phase III trials of its opiate REMOXY, an encapsulated, water insoluble, highly viscous, twice-daily oral formulation of oxycodone. The study met its endpoints, finding that patients did not like REMOXY as much as oxycodone, and could not chew it for more than 1.5 minutes, due to its unpleasant taste and texture. For this class of drugs, developing one that’s liked less than the competitor, and tastes terrible represents a rousing success.

Drug maker KV Pharmaceuticals has been in the news concerning pricing of its newly approved drug, Makena.  Makena, while newly approved, is a version of a very old drug, synthetic progesterone, which had previously been available to consumers for as little $10-$15 a treatment through specialty pharmacies that compounded the drug on site.  On Feb 3, 2011, KV received approval for Makena, an injectable form of synthetic progesterone, under FDA’s Orphan Drug Act, as a treatment for women who are at risk of preterm labor.  Under the Act, KV was awarded seven years of exclusive patent protection. When Makena hit the market, KV set the price at $1500 a treatment and informed compounding pharmacies that they would be in violation of their patent if they continued to supply the generic form of the drug.

Progesterone is given as a weekly shot to women who are at risk of preterm labor, so, at KV’s proposed price, the cost of treatment for the average full-term pregnancy could run as high as $30,000.  An outcry among physicians, patient advocacy groups, and public health officials ensued, which resulted last week in KV dropping the price by more than half and instituting a series of rebates and assistance programs to ensure that consumers would have access to more affordable treatment.  In addition, in response to the public outcry, FDA clarified that in this particular instance, it would not prevent compounding pharmacies from making a generic version available.

Unlike the pricing of consumer goods, drug pricing is completely opaque. In addition to the direct cost of goods, drug companies factor in the large but murky costs of development, which include the costs associated with drugs that don’t make it to market.  To make it even less transparent, price for the same product fluctuates depending on regional markets and negotiated pricing.  The Makena story might easily be viewed as a story of corporate greed, but I’d rather view it as a story of the power of the marketplace. KV was perhaps overly optimistic in setting the price of their product, but was brought back in line by the realities of the market.

Nanomedicine manufacturer Midatech Group (Oxford, England) and drug-delivery company MonoSol Rx (Warren, NJ) recently filed a provisional US patent application for “Nanoparticle Film Delivery Systems” that could transmit proteins and peptides through buccal or sublingual administration. The delivery system bypasses the gastrointestinal (GI) tract and sends medicine directly into the bloodstream. This mechanism could reduce side effects and prevent the GI tract from destroying the therapy.

About two weeks ago, the Georgia Institute of Technology gave Vyteris (Fair Lawn, NJ) the option to exclusively license its patented thermal-ablation and microdevice-fabrication technologies for transdermal drug delivery. The technology was developed to enhance skin permeation to the point where drugs with high molecular weight could be administered without injections or infusions.

These and other new technologies could one day challenge the dominance of injections as a method for administering vaccines. Considering how rapidly the market for vaccines is growing, drugmakers would do well to take notice of these exciting developments. Vaccinations might soon become as painless as freshening the breath with an oral strip. Maybe needles’ days are numbered.

The Reference Standards Symposium began in 1996 and is held every one to two years. Traditionally, the event is hosted by a large pharmaceutical company, but in 2008, the pharmacopeial bodies were invited to play a larger role, and the European Directorate for the Quality of Medicines (EDQM), which is responsible for the European Pharmacopeia, hosted the event (a recap can be found here and the proceedings here). Now, it seems, it’s USP’s turn.

The meeting provides representatives of regulatory and standard-setting bodies (including those in Europe, China, Japan, and North America) as well as industry with an open forum to discuss compendial issues, and to network, and share best practices, according to a website about the meeting’s history. The World Health Organization also attends the symposium. The symposium is meant to help guide the pharmacopeias in the making of reference standards and in harmonization efforts.

The agenda for this year covers regulators’ expectations for quality systems, challenges tied to complying with global regulation, the use of metrological principles to guide reference standards, and control strategies to ensure drug product quality (view the full agenda).

This year’s event may be especially important for symposium participants given the various challenges facing the pharmacopeia during the past year. For example, USP had to recall the entire USP 33–NF 28 issue in November 2009 because of errors in the publication. The US-based pharmacopeia is still working on its revision to the metal-impurities chapters (an effort that began back in 1995). ICH has since formed a working group on the same subject, and the European Medicines Agency is simultaneously working on its metal-residue limits.

In addition, industry is watching the European Pharmacopeia closely regarding its decision to allow different techniques for the production of water-for-injection. There are growing global concerns regarding potential drug-ingredient contaminants (e.g., DEG, melamine) and the revision of related standards and monographs.

Although the pharmacopeia have made great progress over the past few years (e.g., quickly revising the heparin monographs and harmonizing pharmacopeial texts through ICH Q4 and its various annexes), there is much to discuss at this year’s symposium. It will be interesting to see what comes out of the meeting.

Editor’s Note: For clarification purposes, the symposium is dedicated to reference materials rather than documentary standards.   This blog post was updated Sept. 15, 2010.