Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

Most of the products affected by growing drug and ingredient shortages are cancer medications, anesthetics used for patients undergoing surgery, emergency medications and intravenous electrolytes. Sterile injectables, which dominate short-supply lists globally, are prime targets for shortages because of limited production lines and capacity challenges. Everything from manufacturing delays, to increased market demand, to product discontinuation can cause a shortage problem. Unfortunately, it's the patients who need these crucial drugs who are bearing the brunt of the problem. 

In the US, FDA is tackling the issue with new guidance. A recently issued draft document, 

Notification to FDA of Issues That May Result in a Prescription Drug or Biological Product Shortage,

 is meant to address growing concerns by increasing communication between industry and regulators. The draft guidance clarifies that the "sole manufacturer" (i.e., the only applicant currently supplying the market with the drug product) holds responsibility for reporting such information. The document also calls out certain actions that may lead to a temporary or permanent drug supply problem, such as delays in acquiring active or inactive ingredients, equipment failures and manufacturing shutdowns. Manufacturers will need to notify FDA of these issues if they could lead to disruption in supply. The agency also asks industry to notify it on a voluntary basis when certain problems (e.g., stability concerns, facility transfer) could "reasonably" be expected to lead to a shortage or disruption.  

I have high hopes for solving the global drug supply problem. In 2010, for example, 38 shortages were prevented in the US alone because companies notified FDA of potential problems. Meanwhile, in the UK, where parallel trade has led to certain drug shortages, the Medicines and Healthcare products Regulatory Agency has pledged to address shortages and is working to better track which products are in short supply and who is exporting them. As long as companies do their part, these regulatory efforts should pay off. Just as we tell our children, it's always best to tell the truth—even if it hurts a little to do so—because in the end, it's simply the right thing to do. 

Angie Drakulich is the editorial director of PharmTech Europe.

Articles

Most of the products affected by growing drug and ingredient shortages are cancer medications, anesthetics used for patients undergoing surgery, emergency medications and intravenous electrolytes.

The Truth About Drug Shortages

PTE: One tool for bioavailability enhancement is to create amorphous solid dispersions through processes such as hot-melt extrusion (HME) or spray drying. What factors come into play to decide whether to produce the amorphous solid dispersions through HME or spray drying?  

 Both spray drying and HME can be used to produce amorphous dispersions that enhance the bioavailability of poorly soluble compounds. There are a number of factors that come into play when deciding to progress an amorphous dispersion. These include performance, projected dose, stability and manufacturability. When choosing which technology to employ for optimising the amorphous dispersion formulation's performance, two key factors are the physical-chemical properties of the API and the phase of development, which influences the amount of API available for formulation development. 

Important physical–chemical properties include the solubility of the API in either a solvent (for spray drying) or polymer (for HME), the melting temperature of the API and the LogP value of the API. For spray drying, the solubility of the API in the solvent is crucial to ensure a readily scalable and viable process, whereas for HME, the solubility of the API in the polymer is crucial to ensure a thermodynamically stable system. The particle size of the API, which influences the dissolution rate during processing, can also be crucial for complete dissolution into the polymer melt. 

The processing temperature is important for HME because the API must either melt to form a dispersion or dissolve through high shear forces into the molten polymer. If the processing temperature is too high, the compound or the polymer used in the formulation can degrade. Typically, 200 °C to 225 °C is regarded as the upper processing-temperature limit for an effective HME process. Although compounds can be extruded at higher processing temperatures, this physical situation often produces a partially crystalline formulation instead of an amorphous dispersion. 

The phase of development is also an important factor in process selection. For example, for early-stage or discovery-support activities, API availability is often limited. This limited API availability tends to make spray drying the preferable process because its feasibility can be determined with as little as 50 to 100 mg of API, whereas several grams of API are typically required to develop an initial HME process. For APIs that are amenable to HME, typically after proof-of-concept clinical studies, when hundreds of grams of API are available, an initial spray-drying process can be converted from spray drying to HME. 

Advantages and disadvantages of each technique

PTE: What are the advantages and disadvantages of using HME compared with spray drying to produce the amorphous solid dispersion? 

 HME has two primary advantages. First, no solvents are used, so solvent cost and recovery are not a factor in cost-of-goods or environmental health and safety considerations. Second, the equipment footprint for HME is relatively small when the process is scaled up. 

The primary disadvantage of HME is that the compound must be melted or dissolved in molten polymer at high temperatures. Thus, it is less applicable to compounds with higher melting temperatures or those that are thermally labile. This disadvantage can be partially remedied by including nonvolatile and volatile plasticisers in the formulation, which lower the temperatures required to produce an amorphous dispersion. Because an ideal amorphous dispersion is homogeneous at the molecular level, a second disadvantage is that the homogeneity of the final dispersion can be affected by process parameters such as temperature, screw configuration, screw speed and feed rates; this aspect, combined with the relatively large minimum batch size, results in cost and risk during early development. 

PTE: What are the advantages and disadvantages of using spray drying compared with HME to produce the amorphous solid dispersion? 

 Spray drying offers the following advantages: it is applicable to a broader chemical space for the API and types of dispersion polymers that can be used (due to dissolution of the API in a volatile organic solvent), it does not expose the API to excessive heat during manufacture of the amorphous dispersion and it can be scaled down, requiring smaller quantities of API during formulation screening. 

Spray drying has a few disadvantages as well: solvents are used and must be recovered, equipment footprints are larger, and capital and operating costs are higher. These considerations must be taken into account when designing later-stage or commercial processes and facilities, but they are not insurmountable—as evidenced by successful operation of Hovione's PSD-4 and PSD-5 spray-drying facilities and the fact that spray drying is used extensively outside of the pharmaceutical industry at large scales.  

PTE: Can you be specific in terms of achieving desired bioavailability/solubility of the resulting product, stability of the resulting product, the ease and/or scalability of the manufacturing process, and other process conditions that are important in deciding which approach to use?

As mentioned previously, both spray drying and HME can be used effectively to manufacture amorphous dispersions. A formulation produced by either process would be expected to yield similar bioavailability and physical stability as long as both processes yield a homogeneous amorphous dispersion with appropriate final-powder particle size, which generally requires milling for HME. If either of the processes fails to produce a homogeneous amorphous dispersion, the resulting formulation will likely underperform. This situation is most common when a compound fails to completely dissolve during the hot-melt-extrusion process due to either the high melting temperature of the compound, or the low solubility of the compound in the molten polymer, resulting in crystallisation or phase separation when the melt cools. 

Spray drying and HME are readily scaled and commercial-scale equipment is available at many pharmaceutical organisations and several contract research organisations. 

PTE: On an industry level, can you highlight recent advances in HME with respect to improvements in the manufacturing process and its application to different types of APIs? 

 HME is a technology that has been widely used in pharmaceutical and nonpharmaceutical industries for decades. Recent advances in HME include efforts to reduce processing temperatures by including plasticisers and reduce the residence time of the compound and polymer during processing. Numerous research groups are looking at nonvolatile plasticisers, such as vitamin E or triethyl citrate, to reduce processing temperatures. Others have reported the use of volatile excipients, such as supercritical carbon dioxide, to avoid decreases in the final dispersion's glass-transition temperature that occur with traditional plasticisers. There have also been recent reports of the use of equipment that has significantly reduced residence time. Professor McGinity's research group at the University of Texas has developed a process called Kinetisol to make amorphous dispersions. It is based on equipment that was developed to recycle plastics, which can reduce the residence time of the API and polymer at processing temperatures from minutes to tens of seconds. 

PTE: On an industry-wide level, can you highlight recent advances in spray drying with respect to improvements in the manufacturing process and its application to different types of APIs? 

While spray drying is a well-established process, innovations in formulation approaches and process equipment are occurring. In formulation, there is an increasing need for a third component in the dispersions to help deliver challenging compounds aimed at novel biological targets. Often, a surfactant is added to help increase the dissolution rate or dispersion-particle wetting or to provide an alternate micelle source to enhance drug solubility in vivo.  

Equipment advances include novel spray-dryer and cyclone designs to collect the dispersion particles more efficiently. This is especially significant for particle-engineering applications such as inhalation, which requires the manufacture and collection of particles with a narrow particle-size distribution for delivery to the lung. As part of the effort to formulate compounds with low solubility in organic solvents, Bend Research has developed a "hot process," which allows a drug suspension to be heated to high temperatures—often well above the ambient-pressure boiling point of the solvent—in a heat exchanger to dissolve the drug immediately before it is introduced into the spray dryer. This decreases solvent use and results in a more scalable process. 

Enhancing bioavailability can be achieved through hot-melt extrusion (HME) or spray drying.

Bioavailability Enhancement: When to Use Hot-Melt Extrusion versus Spray Drying

	If your company has ever received a 483 from FDA, you likely had a ton of questions about how to respond, how to make things right, and fast.  With new agency enforcement policies in action since 2009, companies are 

 to respond to 483s within 15 business days.  What’s the best format for reporting back to FDA? How will a company know if its response is thorough enough? David Elder, who works in strategic compliance consulting at PAREXEL International, answers these questions in a recent issue of Pharmaceutical Technology. Elder is a former senior official with FDA.

	“It has always been in a company’s interest to respond in writing to an FDA–483, List of Inspectional Observations, issued at the conclusion of their inspection. In so doing, the inspected company demonstrates to FDA that it understands the inspectional observations and that it is committed to implementation of corrective and preventive action. A thoughtful, complete, and timely response establishes credibility with FDA.” Read the rest of his response 

If your company has ever received a 483 from FDA, you likely had a ton of questions about how to respond, how to make things right, and fast.

Received a 483? The Clock is Ticking.

This week, industry members and experts gathered in Philadelphia for two days of informal presentations and discussion regarding biopharmaceutical manufacturing partnerships. The event, hosted by PharmTech and CBI, addressed many common challenges facing the outsourcing sector while also offering potential solutions. Below are a few soundbites from the second day’s discussions (see 

		• Tech transfer timelines need to be aggressive but realistic.
		• Sponsors spend most of their time mitigating deviations. The worst deviations are those affecting post commercial lots.
		• Data trending is lagging across the industry. More is needed to capture and analyze needed data, flexible data, in real time.
		• Equipment and facilities can cause just as many quality problems as the science itself. And Human errors top the list.
		• One big pharma rejected a batch because the data outlied historical trends even though it was in spec. Was this necessary? If this happens often, how does design space and moving within the space then offer benefit?
		• Big pharma is opting to invest smaller dollars in virtual R&D operations to save costs in the long run.
		• The FDA process validation guidance calls for a move from an event mentality to a life-cycle mentality.
		• Process capability and process stability are very different although are sometimes confused and/or mixed up. It’s important to understand each fully and how they impact your product.
		• There is huge variability among CMOS in terms of understanding QbD still. Some say it will take 25 years, or about a generation, for QbD to be common among all facets of the industry.
		• Is QbD a competitive advantage for CMOs? Most say yes.

This week, industry members and experts gathered in Philadelphia for two days of informal presentations and discussion regarding biopharmaceutical manufacturing partnerships.

PharmTech Biomanufacturing Partnerships Conference: Key Outsourcing Thoughts

Tomorrow opens the Biopharmaceutical Manufacturing Partnerships conference in Philadelphia, in coordination with CBI and Pharmaceutical Technology magazine. Experts are expected to speak on number of key outsourcing issues including effective due diligence, good procurement practices, QbD implementation, tech transfer strategies, and emerging business models.

		I’ll be there as will be Patricia Van Arnum, our executive editor. Hope to see you there, and if you can’t make it, stay tuned for reports from the live show.

Tomorrow opens the Biopharmaceutical Manufacturing Partnerships conference in Philadelphia, in coordination with CBI and Pharmaceutical Technology magazine.

Biopharma Manufacturing Partnerships

It’s no secret that excipients are not manufactured specifically for pharmaceutical use. In fact, pharma appears pretty low on many excipient makers’ lists of clients. But their importance in drug formulation and in ensuring final product quality has been gaining recognition over the past few years, unfortunately due to some specific events of contamination and adulteration. Because of growing concern in how excipients function and perform, the US Pharmacopeia has developed a new general information chapter on this topic, chapter <1059>.

		The pharmacopeia is going to talk about the chapter and what it means for industry at its upcoming Science & Standards Symposium in September, in Boston. The 

 will focus on excipient performance, including test methods in the <1059> chapter, and how to best select performance tests. FDA perspectives on excipient variability will also be addressed.

		In addition, PharmTech hosted an educational 

 on this topic in April that is available on demand. Speakers include the USP’s Excipient Director Catherine Sheehan, Colocon’s Ian Robertson, Finn Brit Consultant Chris Moreton, and The University of Michigan’s Greg Amidon. USP Expert Lawrence Block is also on the panel.

		What are your company’s concerns about excipient performance? What testing challenges do you face?

It’s no secret that excipients are not manufactured specifically for pharmaceutical use. In fact, pharma appears pretty low on many excipient makers’ lists of clients.