Particle engineering, which involves obtaining the optimal particle size and size distribution as well as other aspects of the particle's morphology and surface characteristics, is used to improve bioavailability and homogeneity for oral solid-dosage drugs and to prepare inhaled therapies. Micronization is the most widely used size-reduction technique, but other technologies include spray drying, wet polishing, and supercritical fluid processing. 

Delivering drugs directly to the lungs is widely used for local delivery of pulmonary drugs (e.g., for asthma) and is also beginning to be used for systemic delivery as an alternative to oral solid-dose and parenteral drugs. "The increasing popularity of pulmonary delivery can be linked to increasing evidence for the viability of this route of delivery, not only for small molecular weight drug substances but for biotech-derived therapeutic agents and higher molecular weight drugs such as peptides," says Peter York, chief scientist at CrystecPharma. "In addition, there is growing awareness that inhalation can be an attractive option when rapid onset of action is required via systemic distribution."

For systemic delivery, the pulmonary route has the advantage over oral delivery of bypassing hepatic first-pass metabolism, notes Bill Schachtner, associate director, Small Molecule and Inhalation Product Testing Services, PPD. Compared to injectable drugs, inhaled drugs have advantages of patient preference, reduced manufacturing requirements, and reduced need for cold-chain storage, he adds. 

The pulmonary route offers the potential to deliver molecules that would otherwise require parenteral administration, add sources from Hovione. Compared to parenteral administration, pulmonary drug delivery is a convenient, less intrusive alternative, reducing the need for medically trained staff-supervised drug delivery and the cost of producing a sterile drug product. When compared to the oral route, pulmonary drug delivery can use a lower dose with the potential for reduced side effects, they note.


  Particle size is crucial for pulmonary delivery because particles that are too large (> 5 micron) will not go deep into the lungs and those that are too small (< 1 micron) may be exhaled (1). Micronization using jet mills is the most common method of particle size reduction for drug particle engineering, for both oral solid-dosage and inhaled therapies. Micronization is simple, well-established, does not use solvents, and can be used for thermally sensitive materials. However, particles may have amorphous regions that crystallize over time, and particles can be difficult to disperse because of electrostatic charges (1). 

Alternative processes engineer particles by drying them from solution. Emulsion systems create a narrow particle-size distribution, but require high levels of solvents (1). 

Spray drying can be used to engineer particles with specific densities and particle sizes. Because the process uses heat, it is not suitable for some thermally sensitive materials (1). 

Supercritical-fluid (SCF) antisolvent processing employs a supercritical fluid, typically carbon dioxide, as an antisolvent for a solution feed of drug in an organic solvent.  The organic solvent is rapidly extracted by and dissolved in the supercritical fluid, and ultra-fine, crystalline micron-sized particles precipitate rapidly, explains York. By changing the processing conditions, particle engineering and tuning of particle characteristics can be achieved. The process is thus especially suitable for forming engineered particles for inhaled medicines, both in suspension metered dose inhalers and dry powder inhalers, says York. The main advantages over other technologies are that highly crystalline and stable particles are formed, and processing from drug solution to dry particle is a single-step process. In addition the process is highly reproducible and readily scaled, and the drug substance is not exposed to heat, which is an important factor when handling biotechnology-derived drugs, he adds.

Wet-polishing uses a combination of size-reduction technologies and isolation approaches, explained sources from Hovione. The technique can produce specific particle sizes with a precision of ± 0.1 µm and narrow size distribution (1).  The process creates highly crystalline particles with low cohesivity.

Co-crystallization is a new technology that uses novel excipients and processes to create particles of the required size while incorporating excipients to enhance delivery to the lung, explains Schachtner. While some co-crystallization processes use available equipment, other processes use novel equipment. This technology is not yet used for commercially available products. 

Articles

Production Trends

Micronization and other processes are used to obtain optimal particle characteristics for pulmonary and oral solid-dosage delivery.

Need for Particle Engineering Increases

The EdgeTRAC software Print, Apply, and Verify module from ROC IT Solutions is a mobile software solution that can be used in any manual packing operation. The module uses a laptop computer, handheld scanners, and mobile printers. It is designed for repackagers and low-volume manufacturers, as well as high-volume manufacturers who need to serialize a subset of their product line for export to South Korea, China, Brazil, and other countries to meet fast-approaching serialization deadlines. 

Using the module on a smart handheld device, workers scan or enter a product identification for items to be labeled. Next a global trade identification number, lot, and expiry are selected, and serialized 2D-matrix barcode labels containing these standard GS1 identifiers are printed. The module supports any kind of tag format using handheld printers. After workers apply the labels and verify them with a scan from the handheld device, the ROC IT EdgeTRAC software updates all back-end systems with the commissioned serial number hierarchy data.

The module is based on GS1 standards and integrates with any EPCIS-based serial-number management system. Users can also generate and export standard reports for tag status (e.g., printed, verified, not verified, decommissioned).

The EdgeTRAC software Print, Apply, and Verify module from ROC IT Solutions can be used to implement serialization in manual packing operations.

Software Module Prints and Verifies Serialization Codes

With the publicity surrounding the recovery of mold from pharmacy compounding facilities and formulated products connected to patient fungal infections and deaths, there has been a heightened awareness and concern for fungal recoveries in all manufacturing facilities. Humans cannot live in a world that contains at all times substantial concentrations of airborne mold, however, and not be expected to carry some mold along with them as they move from point to point. Mold will be present on clothes, skin, and human hair as a direct consequence of the level of airborne mold that typical individuals inevitably encounter on a daily basis. Reasonable precautions upon moving to sections of facilities where products are aseptically manufactured should include changing into captive shoes and clothing and donning of hair and shoe covers. These precautions, however, cannot be reasonably expected to completely obviate the possibility of random, low-level mold recovery during routine monitoring. There is no medical or toxicological evidence that a low-level environmental mold recovery in a production environment would result in greater risk to a product or end-user than low-level bacterial contamination. Certainly, airborne mold found intermittently and at low frequency is not indicative of mold colonization. Low-level mold likely finds its way into facility environments as a passenger on personnel entering facilities as well as on materials coming into and warehoused within facilities.

To reach spore levels, to say nothing of toxin levels relevant as health risks, mold proliferation (i.e., growth) is necessary. This condition would require a production facility to be infected by mold. Conditions that allow a production facility to become infected are always objectionable. A reasonable question is how would one diagnose the condition of facility infection?


 A facility is infected by the ongoing and consistent presence of mold. Given the microbiological assessments used in drug and biological production facilities, this means high viable recovery levels. There have been reports of building infection even in aseptic manufacturing areas, but fortunately these have occurred infrequently. Those that have been reported were due to water leaks from defective pipes or roofs that soiled wall materials made of sheetrock or drywall panels, which are an excellent food source for mold. The normal course of this type of facility infection is that high counts are recovered over a discrete period of time; the microbiological control team then recommends disinfection of the facility. Disinfection succeeds in a temporary diminution in frequency of recovery and count, but within typically 7–10 days a subsequent bloom is observed, manifested again by atypically frequent recoveries. Additional cycles of disinfection produce similar outcomes, with high counts again appearing within typically one to two weeks post disinfectant treatment. If a sheetrock wall is infected with mold, the only effective remediation is to demolish the walls and reconstruct them with a mold-inhibiting material, such as Plascore pharmaceutical cleanroom panels or fiberglass. 
The recovery levels observed in residential and uncontrolled commercial building infection are unusually high and far exceed the total microbial recovery levels recommended in 

 for classified manufacturing environments (1, 2). Should such conditions be observed in controlled pharmaceutical facilities, an extensive diagnostic program and further steps, including mold remediation, may be necessary. In the event that remediation is necessary, the work that must be done is often extensive, and may require considerable demolition and reconstruction. A mold remediation will be disruptive to operations and may have impact upon manufactured product or work in progress.    


  Mold infections within manufacturing facilities and laboratories may be limited to equipment such as refrigerators or incubators. Again, these are not transient low-level contamination recoveries, but instead are findings reflective of active mold growth. Mold infection of incubators and/or refrigerators has not been uncommon in microbiology laboratories. Fortunately, this is typically an easier condition to treat than wider-spread facility level mold infection.  
A removal of all materials from the equipment followed by careful cleaning and disinfection will in most cases eliminate the infection. Preventive actions include avoiding spillage of organic materials such as media or test materials and where a spill does occur cleaning effectively and at a suitable frequency. Also, to prevent mold infection maintaining dry conditions is key, water spills should be removed quickly, and conditions that favor the formation of condensate should be avoided. In most cases, limited mold infection in support areas, such as laboratories, should not pose significant manufacturing risk, particularly when treated promptly and effectively.


  The key risk factor regarding mold in drug and biological operations is proliferation-driven infection. Infection of facilities or equipment is easily distinguished from transient low-level contamination. Transient low-level contamination will occur infrequently and randomly. There will be no evidence of high-count levels being reached and no indication of persistence. Given the ubiquity of mold in nature and the levels with which they are present in outdoor air or in office complexes, the recovery of an occasional mold does not merit any particular concern.  

On the other hand, evidence of mold proliferation indicative of infection of facilities or equipment must be taken seriously and requires the prompt implementation of corrective and preventive actions. In such cases, the potential effect of mold contamination on product should be carefully assessed.  

In our experience, mold recoveries are typically occurring in industry at levels far lower than bacterial recovery. Certainly, microbiologists should keep a watchful eye on patterns to ensure that they have the means to take note of changes in pattern. It is important that significant microbial changes not be missed or ignored. 


  1. USP, General Chapter <1116>, “Microbiological Control and Monitoring of Aseptic Processing Environments,” (US Pharmacopeial Convention, Rockville, MD, 2012.)
  2. Eudralex, 

Volume 4: EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use: Annex 1: Manufacture of Sterile Medicinal Products

For further information, read the full article, 

Troubleshooting

Understanding how to identify, remediate, and prevent facility infection is crucial for product quality.

Diagnosing Facility Mold Infection

As temperature-sensitive drug products travel worldwide, packaging serves as the barrier to a potentially hostile ambient environment. Temperature-controlled shippers not only maintain payloads within frozen, refrigerated, or controlled-room-temperature (CRT) ranges, but also help brand owners and other supply chain participants meet good distribution practice (GDP) standards. The careful control of payload temperature not only protects product quality, but also reduces losses due to temperature excursions and ensures profitability. 

“There is plenty of evidence that suggests that a product’s temperature (and the associated fluctuations) can have profound impacts on a product’s stability, and therefore, its therapeutic effectiveness,” explained Désirée Valentine, senior supply-chain manager at BioConvergence, a contract service provider offering formulation development, testing, production, and supply chain services, in a statement associated with a presentation at the 11th Annual Cold Chain GDP & Temperature Management Logistics Global Forum, organized by IQPC, Sept. 30–Oct. 4, 2013 in Chicago, IL (1).

 “We are seeing growth in the number of temperature-sensitive shipments due to the increasing cold-chain regulations and expansion of generic products,” said Dirk Van Peteghem, vice-president of UPS Healthcare Logistics, in an announcement discussing UPS’s participation at the same meeting (2).

Other driving forces in the temperature-controlled packaging marketplace include an expanding number of biologics, more attention to CRT distribution, and rapidly growing drug sales in emerging markets. The 

, published by IQPC/Cold Chain IQ, predicts more than 50% of the world’s best-selling drugs will require cold chain protection by 2016. As a result, the study forecasts dramatic growth for the cold-chain logistics market through 2017 with increases of 57% in emerging markets, 46% in Asia, 21% in Europe, and 18% in North America (3). Another market study anticipating strong growth, 

Global Healthcare Cold Chain Logistics Market Report & Forecast (2013-2018)

 by IMARC Group, projects an increase in market value from $7.3 billion in 2013 to $11.4 billion by 2018 (4).

 Despite advances in temperature-controlled logistics technology and best efforts by manufacturers and other participants in the supply chain, problems still occur. For example, Ampio Pharmaceuticals experienced a disruption in its clinical study of Ampion, an injectable anti-inflammatory for knee pain associated with osteoarthritis, when both the study drug and placebo experienced exposure to temperatures below 15 ºC and may have frozen during shipment to clinical sites in January 2014. “Pivotal clinical-trial drug specifications dictate precise temperature and handling conditions for all study drug product in order to assure that the conclusions about the safety and effectiveness of the tested drugs will be accurate and repeatable during routine clinical use,” reported Michael Macaluso, CEO of Ampio in a statement. “The drug temperature specifications were set because Ampion may lose potency if it is exposed to temperatures approaching freezing” (5). Although the cold-chain lapse delayed the release of the analysis of single-injection study data, other aspects of the clinical trial are proceeding as planned, and Ampio is working with FDA to provide acceptable data to support a biologic license application (BLA). As a result, the company anticipates it will file its BLA for Ampion on schedule by the end of the first quarter of 2015 (6). 

 Trends in temperature-controlled logistics include growing availability of prequalified shippers, which simplify the validation process, more sophisticated supply-chain services, rising interest in reusable packaging, and advances in temperature-monitoring technology.


  1. BioConvergance, “BioConvergence Presents Case Study on Temperature Controlled Pharmaceutical Products,” Press Release (Bloomington, IN, Oct. 18, 2013). 
  2. UPS, “UPS Introduces New Shipment Service Levels for Its Temperature True Portfolio,” Press Release (Atlanta, GA, Oct. 2, 2013).
  3. IQPC/Cold Chain IQ, 

, p. 4,  accessed Aug. 12, 2014.  
  4. MarketReportsOnline.com, “Healthcare Cold Chain Logistics Industry 2018 Forecasts Research Report Now Available at MarketReportsOnline.com,” Press Release (Dallas, TX, Dec. 26, 2013). 
  5. Ampio Pharmaceuticals, “Ampio Reports That Due to Temperature Deviations Below Product Specifications During Shipments to the Ampion STEP Study Clinical Sites, Release of Data Will Be Delayed,” Press Release (Englewood, CO, August 21, 2014). 
6. Ampio Pharmaceuticals, “Letter to the Ampio Shareholders in Regard to the STEP Study and Ampio’s Plans for the Ampion BLA,” Press Release (Englewood, CO, August 25, 2014). 

Packaging Addresses Cold-Chain Requirements, 

Hallie Forcinio is Pharmaceutical Technology's packaging editor, 

Packaging & labelling

Use of temperature-controlled packaging is increasing with the growing need for cold-chain protection.

Protecting Temperature-Sensitive Pharmaceuticals

Omega Design and Brazil-based packaging-equipment provider Grupo Tecnor introduced a jointly-developed semi-automatic case packer with unit-level serialization capabilities to the North American market. The ECX-001 Case Packer uses software, cameras, and printers integrated by Omega Design to meet the more stringent track-and-trace requirements mandated by the US Drug Quality and Security Act. 

 The case packer's semiautomatic functionality increases production and eliminates hand-packing costs while avoiding the expensive, often time-consuming transition to fully automatic operations. The machine has a heavy-duty welded tubular construction and uses Allen-Bradley components. The serialization and packing cycle offers maximum safety precautions, such as instant emergency-stop functions, which are important in semiautomatic operating scenarios. Completed cases are automatically discharged onto a free roller table. 

To operate the packer, personnel open an empty case and place it in the loading funnel, where it is held in place to receive individual units. Once the collated units are packed into the case, an integrated camera captures the codes of each individual item and associates them to their case-label code in the serialization software. As this occurs, the operator can monitor the process on a nearby panel view. 

A semi-automatic case packer from Omega Design and Brazil's Grupo Tecnor offers unit-level serialization capabilities.

Equipment and Processing Report-09-17-2014

Need for Particle Engineering Increases

Software Module Prints and Verifies Serialization Codes

Diagnosing Facility Mold Infection

Protecting Temperature-Sensitive Pharmaceuticals

Case Packer Meets Track-and-Trace Requirements