Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	With progress being made in continuous manufacturing of solid-dosage drug products, there is an increasing need for tools to aid risk assessment. In August 2014, FDA awarded a $0.5 million grant to the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) at Rutgers University and another $0.5 million grant to the University of Massachusetts, Lowell (UML) for the development of process simulation and modeling tools for integrated solid-dosage drug manufacturing processes, and work is now underway. The tools will be used for risk assessment of continuous pharmaceutical manufacturing processes, for control strategies, and to identify critical material attributes and process parameters. Continuus Pharmaceuticals, a spin-off company that launched from the Novartis­–Massachusetts Institute of Technology (MIT) Center for Continuous Manufacturing, is taking a different approach and is developing an end-to-end integrated continuous manufacturing process for pharmaceutical products.

	Dr. Seongkyu Yoon, assistant professor in the Chemical Engineering department at UML, is the head of UML's three-year project, which is the university's first project to receive official funding from FDA. The goals of the project are to develop and provide training for process models and a simulation platform, to conduct case studies for quality risk assessment and control strategy determination, and to conduct verification and validation of process models by comparing model predictions with experimental data, reported UML in a press release. Dr. Yoon also leads the Biopharmaceutical Process and Quality Consortium (BPQC) based in the Massachusetts BioManufacturing Center at UML. The BPQC has been working on continuous biopharmaceutical process design and modeling and quality by design and process analytical technology for risk assessment and control strategy determination. The solid-dosage modeling project, which will use the same engineering principles, will be an extension of this research work, notes Dr. Yoon.

	The multiyear project at C-SOPS is focusing on developing flow sheet-model algorithms that dynamically simulate an integrated process from individually developed unit operation models. FDA plans to use these models in the future for risk assessment of process submissions, including failure mode analysis in continuous drug product pharmaceutical manufacturing. 

	C-SOPS has been working on several projects associated with continuous solid-dosage manufacturing since 2006.  At the biannual C-SOPS advisory board meeting in College Park, Maryland on Oct. 29–30, 2014, C-SOPS researchers from Rutgers University, Purdue University, the New Jersey Institute of Technology, and the University of Puerto Rico reported progress on projects and obtained feedback from the C-SOPS industrial consortium, which includes more than 45 companies. Dr. Lawrence X. Yu, acting director of the Office of Pharmaceutical Science at FDA, was the keynote speaker at the meeting. Dr. Yu commended the Center for helping to enable FDA’s vision of the future of pharmaceutical solid-dosage manufacturing in the area of continuous processes, reported Doug Hausner, associate director for Industrial Relations and Business Development at C-SOPS. Dr. Yu further challenged the team to tackle the existing scientific challenges related to pharmaceutical batch manufacturing, indicating that the transition to continuous will take time and many of the scientific approaches used to develop continuous manufacturing are applicable to the challenges that plague batch manufacturing.  

	The project team at the Novartis­–MIT Center for Continuous Manufacturing successfully demonstrated proof-of-concept of its Integrated Continuous Manufacturing (ICM) technology that combines the synthesis of API and final solid-dosage form in a seamless process, and the technology was transferred in 2012 to Novartis, where development is progressing internally. Continuus Pharmaceuticals was launched in 2013 to apply ICM to the broader pharmaceutical industry, and the company has an exclusive license with MIT that is co-exclusive with Novartis. The start-up company has raised $2.5 million in the past two years, notes founder and CEO, Salvatore Mascia, who was formerly the project manager of the Novartis­–MIT Center. Earlier in 2014, the company partnered with pharmaceutical equipment manufacturer IMA Industria Macchine Automatiche, and in November, Continuus announced an alliance with New England Controls, a business of Emerson. In December 2014, Continuus moved into its new process development facility in Woburn, Massachusetts, and the company is ready to begin process development work with clients who want to investigate its novel ICM technology. "We have a pilot process and are ready to go to the next level," says Mascia. He notes that the novel process technology will require a change in operational structure and mindset, but offers significant advantages in efficiency by eliminating the corrective steps required in existing solid-dosage manufacturing. Mascia says that the concept has high-level FDA support.

Articles

FDA funded projects at Rutgers' C-SOPS and at UMass Lowell to develop flow-sheet model algorithms for use in risk assessment, and start-up company Continuus Pharmaceuticals is making progress on their integrated system.

Development Progresses in Continuous Solid-Dosage Manufacturing

Automation, including automated inspection and packaging, is becoming an increasingly important part of pharmaceutical manufacturing. The many benefits of automation include efficiency, saving workers from hazardous environments or repetitive tasks, reducing training overhead, eliminating human error, increasing repeatability and reproducibility, and in cleanrooms, removing the potential for human contamination. 

A robotic system is a type of automation that has multiple axes of motion and can be programmed to perform a function. Robot types include articulated, cartesian (i.e., gantry), parallel (i.e., delta), and selective compliance assembly robot arm (SCARA). Common applications include "pick and place" operations that often use SCARA robots. There is also a new, growing use of delta-type robots for high-speed picking and packaging, noted Chris Sumner, managing director of Fanuc Robotics UK and vice-president of Fanuc Europe Corporation, in a press release (1). Merck, for example, is using a Fanuc delta robot on a bottling line to place dispenser caps onto bottled allergy medications. "Ten variants of the bottle can be run on the system, and the only robot line-change requirement is to select the appropriate program on the robot controller," explained Sumner. 

A study by the Association for Packaging and Processing Technologies (PMMI) found that robots are expected to handle 34% of primary pharmaceutical packaging operations in North America by 2018, compared with 21% in 2013 (2). An increase in the use of robots is seen in dispensing, sorting, kit assembly, and light machine-tending as well as in more traditional applications associated with packaging, notes Jonathan Ferrell, a packaging market manager at ABB Robotics. "The advantages of robotics are fairly simple: greater speed and accuracy, greater flexibility and reliability than hard automation, and they are becoming ever more affordable," says Ferrell. 

Robots for filling, inspection, and packaging


  Robotic technology is being used for vial-filling applications on slower speed applications. "Robotic vial manipulation transfers components from station to station both before and after filling and pack-off," says Walt Langosch, director of sales and marketing at ESS Technologies. The company also has experience with handling plastic and glass prefilled syringes in pre-process, buffering, and initial and end-of-line packaging. "Automated syringe assembly, inspection, and preparation for packaging is an ideal application for robotics," says Langosch. "The primary advantage in sterile environments is reduction of risk due to environmental contamination and contamination generated from human intervention during component transfer."  In addition, productivity is increased because of the accuracy and efficiency of robots, which often perform at increased speeds and produce less scrap. 

Automatic inspection, as part of a robotic system, has the advantage of enabling 100% part inspection. Vision-sensing technology can be used in pharmaceutical packaging to verify serialization numbers for compliance with track-and-trace regulations. "Robotic dexterity and accuracy combined with current and future optical technology and serialization software is the ideal technology for an automated solution," says Langosch. 

An advance in vision sensors is color imaging, which, for example, allows systems to distinguish between bottle caps of different colors, noted PMMI in a trend report (3). Vision sensors have also led to advances in end-of-arm tooling design that improve the ability of robots to accurately identify and place objects.

Robots for producing personalized medicines


Custom automation and contract-manufacturing company Invetech recently partnered with biopharmaceutical company Argos Therapeutics to develop automated manufacturing systems based on Argos' Arcelis technology platform for personalized immunotherapies.  "The Arcelis platform uses two, five-axis robotic arms in the production of the mRNA from a patient’s tumor, which is used as the antigen for loading into the dendritic cells produced in the cellular processing equipment," explains Richard Grant, director of cell therapy at Invetech. "The cellular equipment uses automation to manipulate the white blood cells throughout the manufacturing process to control their development and maturation into dendritic cells. These cells express the desired antigens, which when delivered to a patient, will trigger the patient’s immune system to produce killer T-cells that will target the metastatic tumors."

"The RNA robots manipulate closed disposables to perform the process within the common Class 100,000 cleanroom space," says Grant. "The use of the closed disposables allows multiple patients' materials to be processed in the same manufacturing space, driving the facility capital and operating costs down significantly." 

Argos' lead candidate is currently in Phase III clinical trials, and the automated technology is designed to be modular and easily scalable. Clinical processes are generally manual, skill-based processes that cannot operate practically or economically at commercial scale, notes Grant. Use of robotics, however, allows the processes to be scaled up commercially. "In addition, robotics allows new sites to be replicated around the world in a scale-out model, with minimum training for set-up and validation of new sites and minimal site-to-site variability in production processes," explains Grant.

Robotic technology is ideal for cleanroom processes, such as aseptic filling, because it eliminates human contamination risk. Robotics can provide an ISO 5 environment to preclude the possibility of microbial ingress, says Langosch. ESS Technologies partners with Fanuc Robotics for secondary packaging and palletizing of pharmaceuticals, and Fanuc has several robots that will operate in an ISO 5 environment. The Fanuc M-430iA/2PV can withstand hydrogen peroxide vapor sterilization and has a waterproof rating; all wiring and cabling is routed through the robot’s hollow arm.

Robots designed for use in cleanrooms must minimize particulate generation to maintain cleanroom classifications, typically ISO Class 5 or 6. Cleanability, including minimizing crevices and ensuring the robot is resistant to cleaning and sterilizing agents, is also a requirement, notes Grant. Operator safety must be ensured by guarding or containing the robot. Another requirement is controlling the speed of robot movement to minimize impact on airflow and particle generation and to a lesser extent, managing heat generation and its impact on the heating, ventilation, and air-conditioning system of the cleanroom, explains Grant.


  Robotics has come a long way in the pharmaceutical laboratory, notes Mike Ouren, Life Sciences manager at Precise Automation. In the laboratory, robots are used, for example, to transport microtiter plates between instruments. "Although the instruments can be loaded manually, a robot tied to a scheduling software system eliminates human error, maintains the quality of the experiment, and allows scientists to focus on the content of the experiment, instead of how they will execute it," explains Ouren. 

Laboratories differ from industrial applications in that, although tasks are repetitive, they are not as consistent and may change depending on the experiment, says Precise Automation's Ouren. The need to access equipment near the robot quickly and the space limitations of a laboratory can be met with new collaborative robots that do not require safety guarding. In 2012, Precise Automation introduced a collaborative SCARA robot (or "cobot"), the PreciseFlex (PF)400, which handles less than 1-kg loads and is designed to allow operators to work safely next to the robot without barriers. The smaller footprint of the robot reduces cost, and the space savings is useful in benchtop laboratory applications. The robot is user friendly, and the Precise Guidance Controller inside the PF400 allows laboratory personnel to "teach" the robot using only their hands. "Because there are no barriers, instead of using a complex remote-control pendant to teach the robot, the operator can show the robot what to do by simply grasping the end of the robot arm. This accessibility is unheard of in industrial automation," explains Ouren. 

Other laboratory applications for robots include vial handling. A Fanuc robot is being used in a laboratory, for example, as a single-point handling solution for vial processing. "A handling tool was designed and attached to the end of the robot to enable it to handle ten vials at a time. A variety of components were also placed around the robot cell-including indexing tables for full rack staging, a thermostatically controlled water bath for precise sample temperature, a retrieval system for dumped vials, a washing-brushing-rinsing-drying station, a preservative spray station, and a recapping station," explained Sumner in a press release.

In the laboratory and on the manufacturing floor, robots are increasingly used to improve quality and efficiency. 

PMMI Talks North American Pharmaceutical Trends at interpack

PMMI Packaging Intelligence Brief, "Trends in Robotics: Market Assessment, April 2014," 

www.pmmi.org/files/Research/2014RoboticsPIB.pdf

Robots are proving advantageous in filling, inspection, packaging, laboratories, and the manufacture of personalized medicine.

Using Robotics In Pharmaceutical Manufacturing

Although some aspects of process validation for continuous processes are the same as those for traditional batch processes, there are some unique considerations. Gretchen Allison, senior director and team leader for Global Quality Validation, Pfizer Global Supply, spoke with 

 What are the key considerations for validating a continuous manufacturing process?

Key considerations for validating a continuous manufacturing process rely on many of the established principles of basic pharmaceutical process development, guides, and standards that the pharmaceutical industry generally applies to validating traditional batch processes—for example, the establishment of critical quality attributes (CQAs), critical process parameters (CPPs), and corresponding acceptance criteria for a given product and process. Other process validation considerations that apply to both traditional batch manufacturing and continuous manufacturing are the use of quantitative statistical methods (as appropriate) to evaluate the validation data and the evaluation of intra-batch and inter-batch variation.

System qualification of commercial equipment and other supporting systems, including process analytical technology and/or automation, is also necessary when validating a continuous manufacturing process, and it may be especially critical if some systems are providing real-time monitoring and control.

Considerations for continuous manufacturing process validation should demonstrate that the process is under control and can achieve expected performance. These include start-up and shutdown of the process, process run-time evaluation, and the ability to detect process excursions. Demonstration that the process-control system can reach and detect when acceptable product is produced may include a set of start-up and shutdown activities. The number of start-ups and shutdowns could be determined based on a risk analysis and the unique critical considerations for that process; examples may include process robustness, process flow rate and residence time, and the number and inter-relationship of CPPs/CQAs.  Process validation activities should consider both the optimum process run time and worst case (e.g., longest) process run time to determine if the system can reach and maintain the intended process conditions over the entire process. The ability to detect excursions from the target CPP or CQA values that may require the diversion of non-conforming material should be evaluated. How changes in the process production rate and/or equipment scale impact the process dynamics and whether the process remains in a state of control during commercial manufacture should also be evaluated.

Continuous process verification (per the International Conference on Harmonisation Q8) as an alternative validation approach can use in-line, on-line, or at-line monitoring or controls to evaluate process performance. This approach may be particularly well suited to the evaluation of continuous manufacturing processes and may enable the use of real-time release testing. Monitoring can be combined with dynamic control systems to adjust the process to maintain output quality. This capability also provides the advantage of enhanced assurance of intra-batch uniformity.  Using this approach, data from production batches can essentially support validation with each manufacturing batch, replacing a conventional process validation approach (e.g., three-batch validation at set-point) that was historically used.

: Can you share any best practices around defining a batch/lot in practice?

, a batch/lot of material may be defined by a unit of time or quantity. It is typically defined by a unit of time that corresponds to known flow rate and residence time within the given unit operations of the manufacturing line. Clearly defined criteria are necessary to describe the state of control operation and to establish the lot product and process data (e.g., raw materials and processing conditions used) and material traceability.

 Is real-time release testing able to be implemented at this stage? What are the challenges?

 Pfizer has developed real-time release testing for some marketed products produced in specific manufacturing facilities. The application of real-time release testing is typically product/process specific and is often specific to given manufacturing facilities. Depending upon the specific process, there may be some challenges in the application of real-time release testing that impact the ability of sites to implement real-time release. Examples include:

The ability to perform real-time monitoring, evaluation, and trending of some of the critical attributes and/or CPPs applicable to that product may present some technical challenges if robust selective analytical technologies are not yet developed.  

Ensuring an adequately high sampling frequency for processes with high throughput and low mass/potency to detect potential perturbations that may impact product quality in a real-time manner. 

Ensuring that primary sensors are robust and accurate over the duration of the run, considering, for example, the potential for sensor fouling/buildup of product or sensor failure.

Other reasons why real-time release testing may be challenging include the up-front costs to develop and implement the technology and the limited number of users who have expertise with currently available tools.

Although some aspects of process validation for continuous processes are the same as those for traditional batch processes, there are some unique considerations.

Process validation for continuous manufacturing processes

Experts predict an eventual shift from batch to continuous manufacturing processes. Regulators have expressed support for continuous manufacturing, which is a crucial piece for any pharmaceutical effort. Analytical and manufacturing equipment and control systems have been developed to fit the needs of continuous production, and companies are moving forward. In September 2013, GEA Pharma Systems and G-CON Manufacturing announced a manufacturing collaboration with Pfizer to develop a PCMM (portable, continuous, miniature, and modular) system to create a compact and mobile manufacturing platform for oral solid-dosage (OSD) drugs. The PCMM prototype integrates GEA’s ConsiGma continuous manufacturing platform and MODUL P rotary tablet press, in a 36-ft. wide G-CON autonomous GMP cleanroom structure called a megaPOD. The prefabricated process skid and POD form an environmentally isolated facility that can be installed in standard warehouse space. Maik Jornitz, president of G-CON Manufacturing; Richard Steiner, business development manager for ConsiGma at GEA Pharma Systems; and Michael O’Brien, head of Pharmaceutical Sciences Technology & Innovation at Pfizer spoke with

  What is the status of the PCMM project? 
  


: At the moment, we are working on finishing the industrial skid. The collaboration is more than just a project on paper, we’re creating a tangible process solution that will soon be manufacturing real product. Right now, we’re in the factory acceptance testing phase for the equipment, which is almost finished. Soon the equipment will be combined with the G-CON megaPOD, finally bringing the project from concept to reality.

We are hoping to begin assembly early in the first quarter of 2015 in a Pfizer Groton (Connecticut, US) warehouse. The following are some of the principles that will be demonstrated by the prototype: 

Continuous processing enables steady-state conversion of powder to uncoated tablets within minutes.

Rapid deployment (i.e., design, construction, and implementation of a facility in less than one year with practical options for redeployment) is possible.

Identical equipment can now be used for clinical and commercial manufacturing, effectively eliminating the uncertainty and significantly reducing the costs of traditional development to manufacturing and site-to-site technical transfers.

 What are the advantages of the four aspects (portable, continuous, miniature, and modular) of the PCMM model and how do they relate?

: The key point is that continuous processing is the element that enables process intensification. Continuous processing and the manufacture of smaller product quantities in a continuous manner mean that machinery product-contact surfaces are becoming much smaller. Hence, the equipment is becoming smaller, more portable, and by definition, modular. So, there are four elements: continuous processing is enabling miniaturization; miniaturization is allowing processing systems to become portable and modular. And when you put all that together, you get the PCMM paradigm.

: Continuous processing technologies have been around for more than 50 years. In the pharmaceutical industry, we have been at the point where processing equipment can routinely be configured in a continuous or semi-continuous manner for quite some time. Of greater importance is that our new paradigm shift has enabled dramatic reductions in size (miniaturization), which in turn begets true modularity. Reduced footprint, in combination with true modularity, allows processing trains to be enclosed in dramatically smaller, autonomous, GMP-compliant spaces at a relatively low cost. As a natural consequence, the self-contained processing entity no longer needs a traditional ‘brick and mortar’ factory infrastructure. Portability enables strategically driven redeployment options and allows the facility to be classified such that accelerated capital depreciation is possible.

: The PCMM model is the manifestation of the industry’s vision and need for flexible and rapidly deployable manufacturing systems. Future facilities won’t necessarily be large-scale, dedicated, single-product sites, but smaller, more agile manufacturing facilities that comply with the central tenets of FDA’s “Quality for the 21st Century” initiative. These agile production sites will be modular--or podular--and designed to be mobile. Continuous manufacturing, used in both OSD applications and bioprocessing, will support the benefits that can be gained from miniaturized or small-volume production processes. The PCMM consortium is exploiting all these options to fully optimize the efficiency and flexibility of future production processes.

: What scale is meant by “miniature”?

: We expect to operate within a range of 5 to 30 kg per hour, which roughly translates to an annual capacity of 0.5 to 1 billion uncoated tablets per year.

: Comparing batch processing with continuous systems is difficult in terms of absolute numbers, but the footprint or volume of such a system could be up to 60-70% smaller than a conventional installation. Being continuous actually eliminates the question of scale: the only factor is time. The equipment is physically smaller, but as it’s run continuously, it’s easy to manufacture production-scale volumes of product. There’s no need for scale-up any more or long product transfer times from R&D to full-scale manufacturing.

: What do you see as the biggest challenges in employing the PCMM model?

: From my perspective, I would say that we’ve not really encountered any insurmountable hurdles. Regarding technical challenges, the miniaturization aspect was challenging, but we found solutions. Economically, we’ve discovered that the system price for the PCMM compares very well with traditional models and actually offers a lot of advantages, especially in terms of its portability, flexibility, and productivity. The whole system was put together with existing equipment, including the commercialized CMT continuous inline blending technology from Pfizer. We didn’t have to invent anything new; we’ve just put it together in a smart new way.

: There is a body of work around achieving regulatory understanding and ultimately their acceptance of both the technology and general paradigm. FDA and EMA have expressed  support for and seem to expect broader implementation on continuous manufacturing in the pharmaceutical industry, but many aspects will need to be worked through in terms of what is required for regulatory filings and routine operation. Challenges also remain in moving from the batch test and release to a real-time release paradigm. It is unclear whether regulatory agencies in developing markets will readily embrace the new technology. We also anticipate that workforce planning and retraining will be crucial to the successful implementation of this new paradigm.

: Do you have continuous manufacturing projects outside of PCMM?

: GEA’s ConsiGma is a multipurpose platform for continuous manufacturing that has been designed to transfer powder into coated tablets in development, pilot, clinical, and production volumes in a modular, compact unit. The system can perform dosing and mixing of raw materials, wet granulation, drying, tableting, or direct compression, including online PAT quality control, all in one system.

: At Pfizer, we have a number of ongoing projects in various stages of development that are investigating continuous and semi-continuous processing technologies for both API and other drug product development and manufacturing processes. It should be noted that we are also working with global regulatory bodies to ease the adoption of PCMM and related advanced manufacturing technologies.
  PharmTech: What role do you think continuous manufacturing (PCMM or other) will play in oral solid dosage in the next 5-10 years?

: From our vantage point, it wouldn’t be a surprise to see PCMM and other related OSD continuous development and manufacturing paradigms ultimately become the new norm in the pharmaceutical industry.

: Continuous manufacturing will dominate facility and process designs, as well as the manufacturing modus.

: Continuous manufacturing will continue to grow. The pharmaceutical industry is facing increasing demands for faster supply chains, and continuous technology is an enabler of more flexible and faster routes to market. I reiterate the key aspect that continuous manufacturing is an enabler of miniaturization; the subsequent portability and modularity lead to ‘process excellence,’ which in turn, delivers ‘business excellence,’ saving both cost and time, improving manufacturing efficiency, and enhancing the output quality of the whole organization.

A G-CON, GEA, and Pfizer collaboration developed a PCMM (portable, continuous, miniature, and modular) system to produce oral solid-dosage drugs.

Continuous Solid-Dosage Manufacturing Platform Nears Prototype Installation

Highly potent APIs present several challenges for finished-dosage drug manufacturing because they must be handled in a manner that both protects the drug product from cross-contamination and protects manufacturing personnel. Automation, process analytical technology that allows monitoring without operator contact, and disposable equipment are technologies that offer potential solutions to some of these challenges (1). No matter what equipment is used, however, manufacturers must first assess the risk of cross contamination and exposure. 


A significant issue has been whether manufacturers can use shared facilities for manufacturing highly potent drugs. FDA regulations say that penicillins must be processed in dedicated, segregated facilities, and a 2013 FDA guidance added that beta lactams should also be segregated (2). Other products may be manufactured in shared facilities if precautions are taken to prevent cross contamination or mixups, noted Stephanie Wilkins, president of PharmaConsult US, in a presentation at Interphex 2014 (3). 

The European Medicines Agency (EMA) has updated their GMP regulations, and the final version of Chapters 3 and 5 will come into effect March 1, 2015 (4, 5). The new regulations say that the outcome of a quality risk management process should determine the need for segregated facilities. The risk assessments should address modes of cross-contamination that could occur to be sure that certain thresholds are not exceeded. Dedicated facilities must be used if scientific data from the toxicological evaluation does not support a controllable risk (e.g., for penicillins or beta lactams), cannot control the risks to acceptable levels, or do not have an analytical method that is more sensitive than the relevant residue limits derived from the toxicological evaluation, noted Wilkins.

EMA does not yet have a final guidance for the toxicological evaluation. An EMA draft guidance on manufacturing in shared facilities (6), however, outlines how to determine threshold values or permissible daily exposures (PDEs) that can be used to set limits for unacceptable cross-contamination. Alternatively, the International Society of Pharmaceutical Engineering (ISPE) 

 provides guidance on how to determine acceptable daily exposures (ADEs) that can also be used to set the limits (7). These limits are more appropriate than previous limits, which may not be stringent enough to protect workers or product quality for highly potent compounds, said Wilkins. 


  In a risk assessment, companies must examine various routes of cross-contamination. These routes include mixups, carryover, and mechanical or airborne transfer, Wilkins explained in her presentation. 

An example of a mixup is a wrong label on a product. Mislabeling does occur. In September, 2014, for example, Baxter initiated a voluntary recall of one lot of injectable product due to a labeling error on a shipping carton (8).  

With shared equipment that is cleaned between different materials, material retained in equipment could be carried over into the next product, resulting in cross-contamination. The big change in regulations here, explained Wilkins, is using health-based limits based on ADE, acceptable daily intake (ADI), or PDE thresholds to determine what the limits should be for confirming that cleaning processes are effective to prevent retention and carryover. ISPE’s Risk-MaPP Baseline Guide offers a scientific, risk-based approach to determining and managing cross-contamination using ADE, which is similar to PDE (7). 

Mechanical transfer can occur if residue escapes the process (e.g., a spill onto the floor), where it could be transferred, for example, by operators’ shoes or gloves. Airborne transfer can occur if residue escapes the process and is in the air, where it could be transferred through the air-handling system. Controls must be set to prevent cross-contamination through any of these routes, noted Wilkins in the presentation. In addition, the new EU GMPs now require a risk assessment of these controls to be able to confirm that these products can be safely manufactured in shared facilities.

C. Challener, "Technology Choices in Highly Potent Solid Dosage Manufacturing," Jul. 2, 2013, 

www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=817278

Guidance for Industry: Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination

S. Wilkins, "Using Shared Facilities for Manufacturing High Potency Finished Drugs," Presentation at Interphex (New York City, 2014).  

EudraLex Volume 4, Chapter 3: Premises and Equipment

Draft Guideline On Setting Health Based Exposure Limits For Use In Risk Identification In The Manufacture Of Different Medicinal Products In Shared Facilities

Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP)

, "Baxter Initiates Voluntary Recall of Potassium Chloride Injection,"  

http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=854254

To hear a recorded interview with Stephanie Wilkins on this subject, watch 

Manufacturers using highly potent APIs must examine cross-contamination routes and determine acceptable limits.

Evaluating Cross-Contamination Risk of Highly Potent APIs

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. 

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