Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	The challenge of developing orally inhaled nasal drug products (OINDPs) is complicated by the interplay between drug-delivery devices and formulation. An article in the February 2013 issues of 

“Improving Inhaled Product Testing: Methods

for obtaining better in vitro-in vivo relationships,”

 discussed testing equipment and techniques. 

 recently interviewed the author, Mark Copley, sales director at Copley Scientific, to gain further insight into the importance of this topic.

: What are some of the challenges in correlating device and formulation characteristics with clinical efficacy for OINDPs?

First, with OINDPs, successful drug delivery depends a great deal on the technique and health of the user. With a passive dry-powder inhaler (DPI), for example, an instruction to “inhale strongly and deeply” will result in the application of different amounts of energy for dose dispersion according to the strength and physiology of the user and any lung function impairment. Furthermore, the dispersive effect this produces depends on the characteristics of both the device and the formulation, complicating the ability to predict performance.

	Second, there are challenges in establishing 

 tests that accurately represent the complex diffusion, sedimentation, and impaction mechanisms of deposition that occur in the throat and lungs. Cascade impaction, for example, is a very useful and widely applied technique, but the aerodynamic particle-size data it provides is indicative of likely 

 deposition behavior only; direct equivalence is not observed.

	Finally, extending deposition behavior to draw conclusions about clinical efficacy is further complicated by factors such as the variability in clinical response that arises from loss of airway patency.

 relationships (IVIVRs) for OINDPs is far more complex than for other pharmaceutical products such as tablets.

What factors are prompting current efforts to enhance inhaled product testing?

 One driver for enhanced testing is the extension of OINDP technology to patient groups who may achieve lower delivery efficiencies than are indicated by the standard tests. This includes pediatric or older-age users, for example.  Another is the use of OINDPs to deliver drugs that act systemically, for which it is particularly important to engineer robust delivery. More generally, enhanced testing supports the development of newer, more sophisticated OINDPs with more closely defined performance profiles.

	For the generics sector, minimizing the extent of clinical trials is a challenging but valuable goal. Here, new 

points to the possibility of demonstrating bioequivalence through 

 testing alone. However, this depends on rigorously demonstrating the relevance and validity of the test methods applied and similarly places emphasis on ensuring that tests are as representative as possible.

 If you had to highlight just one of the techniques for refining testing that you discuss which would it be and why?

It would have to be the application of breathing simulators combined with more representative upper airway (inlet) geometry, because of the interest that this is generating in the inhalation community, and because I think that this approach will substantially enhance our understanding of OINDP performance. The use of more representative breathing profiles is especially helpful for DPIs, which are complex to engineer. Here the use of breathing simulators enables researchers to fully scope the variability that may arise from patient capability and technique, supporting a quality-by-design approach and the successful implementation of OINDP technology for all user groups.

	For more information, read Mark Copley’s article, 

“Improving Inhaled Product Testing: Methods for obtaining better in vitro-in vivo relationships.”

Articles

The challenge of developing orally inhaled nasal drug products (OINDPs) is complicated by the interplay between drug-delivery devices and formulation.

Improving Inhaled-Product Testing

The conference schedule at INTERPHEX 2013 covers a wide range of topics, including facility and process design, product development, and regulatory quality assurance. 

 interviewed some of the speakers to get a preview of their presentations. Access the podcasts using the links below.


 Modularization has been used by other industries for decades and, over the last few years, has been more accepted by the bio/pharmaceutical industry. Modularization is fast becoming an essential component of bio/pharmaceutical facility design. Use of modularization is growing because it meets industry needs for reduced cost, accelerated construction schedules, and quality construction. The need for offsite skilled labor to construct hygienic components in a controlled, quality location is increasing, notes Craig Sandstrom, director of process engineering at Fluor, driven in part by the growth of construction in locations such as Asia or South America where local trades aren’t as mature as in North America and Europe. 

The concept of “standardization” in modularization is often misunderstood, comments Par Almhem, president of ModWave and Modular Partners. He explains that a process can be divided into discrete operations with defined inputs and outputs, and a variety of systems can then be made from these standard building blocks (i.e., modules). In the future, modules will be used more widely as a more efficient way of building anything, whether it is a physical building, a software system, or a bio/pharmaceutical process, predicts Almhem.

Sandra Leuken from Baxter Pharmaceuticals, Par Almhen from Modular Partners, Detlef Kehm from Grifols, and Craig Sandstrom from Fluor are part of a panel discussion, “Getting Excited about the Modular Experience” (1:30-3:00 pm Wednesday, April 24).  Par’s presentation is on “Advances in modularization: standardization, modular unit operations, and global deployment,” and Craig’s presentation is titled, “Modularization overview and implementation strategies.”

Access podcasts by clicking here:
 Craig Sandstrom, FluorPar Almhem, Modular Partners

Single-use Systems in Traditional Stainless-Steel Facilities


 Advantages of single-use systems are well known. These include reducing cleaning costs, floor space requirements, and classified-space requirements. One of the biggest advantages, says Jeff Odum, director of operations at IPS–Integrated Project Services, is flexibility, particularly related to process changes in early-stage development. He explains that there are several types of companies that can benefit from the flexibility of single-use systems. These include contract manufacturing organizations (CMOs), research-driven organizations doing high-level development work, and companies focused on pandemic response, all of which need to adapt to new technologies. Academic institutions can benefit from the lower capital requirements. “Any manufacturing organization should explore the potential advantages of this technology,” says Odum. 

The IPS presentation, “Implementing Single-Use Biomanufacturing Systems into Traditional Stainless Steel-based Facilities,” will be held on Tuesday, April 23 from 2:45-3:45 pm.

Access podcast by clicking here:
Jeff Odum, IPS


 The International Conference on Harmonisation (ICH) guidance for industry, Q8(R2) 

Guidance for Industry Process Validation: General Principles and Practices 

describe approaches for development and validation of pharmaceutical processes (1, 2). These concepts can also provide a scientific basis for the development and validation of cleaning processes, says Keith Bader, senior director of technology at Hyde Engineering + Consulting. Cleaning processes have traditionally been developed on full-scale manufacturing equipment using general industry information without real regard for the nature of actual residues and their removal. Validation of cleaning processes, likewise, has in the past relied only on monitoring critical process parameters, such as temperature and concentration of cleaning solution, and using a fixed cycle time rather than using forward-processing criteria to indicate when the cleaning process is complete. Moving forward, however, process analytical technology and better understanding of the cleaning process design space can improve decision making and result in more efficient cleaning, explains Bader. 

Keith’s presentation, “Establishing a design space: cleaning process development and validation,” will be held on Tuesday, April 23, from 11:30 am to 12:30 pm. 

Access podcast by clicking here:
Keith Bader, Hyde Engineering + Consulting

Each company must implement its own continuous validation program (CVP) for its systems based on current FDA guidelines (2). Defining a CVP helps plan and prioritize validation projects and determine personnel requirements and budgets, notes Victor Hernandez, senior process validation engineer, project engineer III, in the Sustainable Engineering department at EMD Millipore in Jaffrey, New Hampshire.  Procedures and policies must be transferred from the corporate level to the division level and to specific sites, where they must be applied to specific manufacturing processes. In his case-study presentation, Hernandez describes how the EMD Millipore Jaffrey site helped bring Merck’s CVP in line with current trends and apply it to EMD Millipore Corporate division and to EMD Millipore separation and filtration device-system manufacturing processes at various sites, following Millipore’s acquisition by Merck KGaA. 
  
 Victor’s presentation, “Current continuous process validation program: following FDA current guidelines,” will be held on Wednesday, April 24 from 1:30-2:30 pm. 

Access podcast by clicking here:
Victor Hernandez, EMD Millipore


 A panel discussion moderated by Pharmaceutical Technology will examine the lessons learned, successes achieved, and ongoing challenges of implementing QbD in pharmaceutical manufacturing.  Dr. John Lepore, senior director of Chemical Process Development and Commercialization for Global Pharmaceutical Commercialization at Merck and Co., will provide expertise on application of design space and control strategies for API manufacturing. Dr. Chris Moreton of FinnBrit Consulting will share his expertise in how to incorporate excipients into the design space. Jonathon Thompson, senior manager of Compliance Services Consulting at Invensys Operations Management will use his experience to discuss challenges in adapting the manufacturing process from a control perspective, including the feasibility of real time release. Together, the panel will consider the benefits of adapting QbD and the challenges yet to be addressed. 

The panel discussion, “Lessons Learned: Successes and Challenges in Implementing Quality by Design,” will be held on Wednesday, April 24, from 10:15-11:15 am. 

Access podcast by clicking here:
Panel discussion

Guidance for Industry, Process Validation: General Principles and Practices

Speakers discuss modularization, single-use systems, and process validation in a series of podcasts available on the Pharmaceutical Technology website.

Experts Give "Sneak Peeks" into INTERPHEX 2013 Conference Presentations

 annual equipment and manufacturing survey gained the industry’s perspectives on trends in finished drug-product manufacturing and equipment. Respondents in both solid dosage and parenteral drug manufacturing were generally satisfied with the utility of existing equipment and the pace of innovation in meeting manufacturing needs. Most employ quality by design (QbD) to some extent, but respondents identified a range of challenges in implementing QbD. This article is excerpted from an article in the April 2013 issue of 

, which further details trends in high-potency/high-containment manufacturing, process analytical technology (PAT), and continuous manufacturing.

Solid-dosage equipment
The survey showed that existing solid-dosage equipment is generally meeting needs. Areas noted by more than 20% of respondents as needing significant improvement, however, included process control/automation, powder transfer/materials handling, and feeding/dispensing (see Figure 1). When asked if innovation is keeping pace with current and future needs, responses were similar, with the same three areas indicated as lacking solutions by 20% or more of respondents. Tablet compression stood out as a strongly innovative area, with 96% of respondents indicating that innovation is “excellent” or “good” for this equipment.

 Users of parenteral equipment, likewise, are generally satisfied with existing equipment, as shown in
Figure 2. Process control/automation and vials/cartridges fill–finish equipment, however, were two areas noted by 20% or more of respondents as needing significant improvement. In all segments, nearly 80–90% of respondents said that the pace of innovation was “good” or “excellent”.

QbD
Almost half of respondents indicated that their company applies QbD principles for both new and legacy products, and another 32% apply QbD to all or select new products (see Figure 3). Only 22% of respondents do not apply QbD at all. Approximately 72% identified better process understanding as a benefit of QbD. Participants were invited to choose all answers that applied, and they indicated other benefits of QbD as increased 

efficiency/reduced waste (48%), reduced costs (44%), shorter process times (35%), streamlining regulatory review (32%), and improved ease of making changes (29%). Only 6% of respondents felt that there are no challenges or barriers to implementing QbD. More than half noted lack of knowledge and training as a problem.

 Equipment and Manufacturing Survey targeted individuals in production and engineering. The survey was conducted by email in February 2013 and had 193 respondents. Nearly 30% were from innovator pharmaceutical companies, 28% from generic-drug companies, 20% from contract manufacturers, and 10% from consumer healthcare companies making over-the-counter products. The remaining respondents included excipient and raw material suppliers (7%) and equipment or machinery vendors (5%). About half of the respondents were involved with solid-dosage manufacturing and the other half in parenteral drug manufacturing. The majority of respondents (79%) were from companies with under $1 billion in revenue. Nearly 7% were from companies with between $1 billion to 10 billion in revenue, almost 7% were from companies with $10 billion to 50 billion in revenue, and the remainder (8%) were from companies with over $50 billion in revenue.

Pharmaceutical Technology's survey of manufacturing equipment and trends shows satisfaction with utility and innovation in most solid-dosage and parenteral drug-manufacturing equipment.

Evaluating Equipment Utility and Innovation

 will be moderating a panel discussion, “Lessons Learned: Successes and Challenges in Implementing Quality by Design,” on Wednesday Apr. 24 from 10:15 to 11:15 at INTERPHEX in New York City. You can listen to a 

 about the panel discussion that is posted on 

	Dr. John Lepore, senior director of Chemical Process Development and Commercialization for Global Pharmaceutical Commercialization at Merck and Co., will provide expertise on application of design space and control strategies for API manufacturing. Dr. Chris Moreton, FinnBrit Consulting, will share his expertise in how to incorporate excipients into the design space. Jonathon Thompson, senior manager of Compliance Services Consulting at Invensys Operations Management will use his experience to discuss challenges in adapting the manufacturing process from a control perspective. Together, the panel will consider the benefits of adapting QbD and the challenges yet to be addressed. I hope to see you there.

Pharmaceutical Technology will be moderating a panel discussion, “Lessons Learned: Successes and Challenges in Implementing Quality by Design,” on Wednesday Apr. 24 from 10:15 to 11:15 at INTERPHEX in New York City.

Panel Will Discuss Quality by Design at INTERPHEX

 interviewed some of the speakers for the upcoming 

 conference to get a “sneak peek” of their presentations. The first of these, an interview with Par Almhem, president of ModWave and Modular Partners, discusses advances in modularization. Check out the media player on the 

 to listen to the podcast, and look for more to come soon. If you’re at the show, be sure to stop by 

Pharmaceutical Technology interviewed some of the speakers for the upcoming INTERPHEX 2013 conference to get a “sneak peek” of their presentations.

INTERPHEX Conference Previews

’s annual equipment and manufacturing survey gained the industry’s perspectives on trends in finished drug-product manufacturing and equipment. Respondents in both solid dosage and parenteral drug manufacturing were generally satisfied with the utility of existing equipment and the pace of innovation in meeting manufacturing needs. Most employ quality by design (QbD) to some extent, but respondents identified a range of challenges in implementing QbD. Responses also indicated trends in high-potency/high-containment manufacturing, process analytical technology (PAT), and continuous manufacturing. 

 Figure 1: Utility of existing solid-dosage equipment in meeting needs (% of respondents).The survey showed that existing solid-dosage equipment is generally meeting needs. Areas noted by more than 20% of respondents as needing significant improvement, however, included process control/automation, powder transfer/materials handling, and feeding/dispensing (see Figure 1). When asked if innovation is keeping pace with current and future needs, responses were similar, with the same three areas indicated as lacking solutions by 20% or more of respondents. Tablet compression stood out as a strongly innovative area, with 96% of respondents indicating that innovation is “excellent” or “good” for this equipment. 

Figure 2: Utility of existing parenteral equipment in meeting needs (% of respondents).Users of parenteral equipment, likewise, are generally satisfied with existing equipment, as shown in Figure 2. Process control/automation and vials/cartridges fill-finish equipment, however, were two areas noted by 20% or more of respondents as needing significant improvement. In all segments, nearly 80-90% of respondents said that the pace of innovation was “good” or “excellent”. 

High-containment/high-potency manufacturing

Just over half of respondents that are involved in high-containment/high-potency manufacturing had seen an increase in activity in this area in the past year. Approximately one quarter of respondents said system setup/changeover was the most challenging factor in high-containment/high-potency manufacturing, while another quarter identified getting materials into or out of the contained system during production as the most challenging. Others identified air flow (10%), air-flow changes (10%), environmental issues (10%), containment (10%), personnel protection (7%) and ergonomics (3%) as the most challenging factor in high-containment/high-potency manufacturing. 

 Figure 3: Application of quality-by-design (QbD) principles to manufacturing processes (% of respondents).Almost half of respondents indicated that their company applies QbD principles for both new and legacy products, and another 32% apply QbD to all or select new products (see Figure 3). Only 22% of respondents do not apply QbD at all. Approximately 72% identified better process understanding as a benefit of QbD. Participants were invited to choose all answers that applied, and they indicated other benefits of QbD as increased efficiency/reduced waste (48%), reduced costs (44%), shorter process times (35%), streamlining regulatory review (32%), and improved ease of making changes (29%). Only 6% of respondents felt that there are no challenges or barriers to implementing QbD. More than half noted lack of knowledge and training as a problem. Approximately 42% indicated clarity of regulatory guidance as a barrier. Only about one-third of repondents chose, respectively, lack of management buy in, availability of software, or availability of equipment as barriers to QbD implementation. 

 Figure 4: Current and future use of process analytical technology (PAT) (% of respondents).Over half of respondents indicate that they use PAT, which is an increase from last year’s survey that found only 40% of respondents incorporating PAT (1). When asked to indicate the primary drivers for using PAT (multiple answers permitted), nearly half of respondents chose increased efficiency/reduced waste; others chose better process understanding (44%), reduced costs (33%), and shorter process times (31%). Almost 10% indicated that their company mandates use of PAT, and nearly 6% said their customers request it. Sterile manufacturing/aseptic processing and lyophilization are areas of potentially strong growth for the use of PAT. As shown in Figure 4, 14% of respondents in these areas use PAT now, but an additional 50% plan to implement PAT in the coming year. Compared to the other categories, a higher percentage in solid-dosage manufacturing (22–26%) already use PAT, but a lower percentage (24–25%) plan to add PAT in the coming year. 

Continuous manufacturing is still a new technology, but is being considered as an alternative to traditional batch processes for solid-dosage manufacturing. Respondents indicated (multiple answers permitted) multiple barriers to implementing continuous processes, including:

lack of appropriate documentation systems (15%). 

Nearly all agreed, however, that technology will continue to evolve and use of continuous processing will increase. 

Pharmaceutical Technology’s Equipment and Manufacturing Survey targeted individuals in production and engineering. The survey was conducted by email in February 2013 and had 193 respondents. Nearly 30% were from innovator pharmaceutical companies, 28% from generic-drug companies, 20% from contract manufacturers, and 10% from consumer healthcare companies making over-the-counter products. The remaining respondents included excipient and raw material suppliers (7%) and equipment or machinery vendors (5%). About half of the respondents were involved with solid-dosage manufacturing and the other half in parenteral drug manufacturing. The majority of respondents (79%) were from companies with under $1 billion in revenue. Nearly 7% were from companies with between $1 to $10 billion in revenue, almost 7% were from companies with $10 to $50 billion in revenue, and the remainder (8%) were from companies with over $50 billion in revenue. 

1. P. Van Arnum, Pharm. Techol. 36 (4) 50-60 (2012). 

A Pharmaceutical Technology survey shows satisfaction with utility and innovation in most solid dosage and parenteral drug-manufacturing equipment.