Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

The International Society of Pharmaceutical Engineering (ISPE) released guidance for the design, construction, and commissioning and qualification of packaging, labeling, and warehousing (PACLAW) facilities.  The

 ISPE Good Practice Guide: Packaging, Labeling, and Warehousing Facilities

 helps companies meet cGMP requirements for PACLAW facilities and avoid problems such as product adulteration, product mix-up, label mix-up, and misbranding.

“PACLAW facilities are very different from other types of pharmaceutical facilities, and up until this point, there has been no consistent guidance available to help companies ensure compliance,” said guide author Nick Davies in a July 3, 2012 press release. “With this ISPE guide, the industry finally has tools to ensure their PACLAW processes are efficient, compare their processes to established best practices, and demonstrate compliance to regulatory agencies.”

The guide gives direction on designing or reconfiguring PACLAW facilities using quality-by-design principles. It also explains how PACLAW facilities can comply with FDA’s systems-based approach, which uses a risk-based inspection model. 

Articles

ISPE has issued a guidance that is intended to help companies meet cGMP requirements for packaging, labeling, and warehousing facilities and avoid problems such as product adulteration, product mix-up, label mix-up, and misbranding.

ISPE Issues Guidance for Packaging, Labeling, and Warehousing Facilities

	Continuous manufacturing is the way of the future for solid-dosage pharmaceuticals, but one of the challenges for implementation is how to define a batch for quality assurance testing.  There are also other, related questions. When you are running one product continuously, where do you draw the line between out-of-specification start-up or transition material and in-spec product? What can you do about this lost, out-of-spec material? How do you test for quality and maintain data integrity? Other industries that have moved from batch to continuous, such as plastics and food, resolved these issues long ago, and some parts of the pharmaceutical industry have done it too. Some tablet coating is continuous, particularly in cosmetic vitamin coating. Excipients are produced continuously. How can those seeking to move to continuous manufacturing translate what has already been learned to their own application? I’d like to hear from those working in this area. What are the challenges and unresolved questions you face in this task?

Continuous manufacturing is the way of the future for solid-dosage pharmaceuticals, but one of the challenges for implementation is how to define a batch for quality assurance testing.

Defining a Batch in Continuous Manufacturing

What are the key developments that have influenced solid dosage and sterile manufacturing during the past 35 years and the technologies that will shape its future? 

 spoke to leading scientists, equipment manufacturers, and senior production executives to gain their perspectives. Offering insight on solid-dosage manufacturing are Chris Moreton, PhD, vice-president of pharmaceutical sciences at FinnBrit Consulting and a member of the 

Editorial Advisory Board; Charles Kettler, PhD, director of Natoli Scientific, a division of Natoli Engineering; and from Pfizer, Axel Knoch, senior director and team leader of product and process development; Cynthia Oksanen, director, PharmaTherapeutics R&D; and John Groskoph, senior director, global chemistry manufacturing and controls. Providing perspectives on sterile manufacturing are James Agalloco, president of Agalloco & Associates and a member of the 

 Editorial Advisory Board; Ryan Hawkins, vice-president and chief operating officer at Cook Pharmica; and Bernd Stauss, vice-president of production & engineering at Vetter. 

What would you identify as the most significant advances in solid dosage manufacturing in the past 10 years? 

The evolution of new formulation techniques that allow poorly soluble molecules to press forward as potentially effective treatments for patients is a significant advance.  

Figure 1: Industry roundtable participants, from left to right: Chris Moreton, PhD, vice-president of pharmaceutical sciences at FinnBrit Consulting and a member of the Pharmaceutical Technology Editorial Advisory Board; Charles Kettler, PhD, director of Natoli Scientific, a division of Natoli Engineering; and from Pfizer, Axel Knoch, senior director and team leader of product and process development, and Cynthia Oksanen, director, PharmaTherapeutics R&D. 			

There have been several incremental advances, such as improvements in cleaning, which allow shorter changeover times when switching to another product, and developments in sensor technology for granulation, blending, and compaction. However, traditional batch processing is very inefficient because the equipment is idle for significant periods of time. The most significant advances, therefore, have been in beginning to apply continuous manufacturing methods.  

The main advances have involved the application of advanced materials science and engineering tools to enable greater understanding and heightened control of existing unit operations. Measurements of the material properties of APIs and excipients are now routinely applied to the design of manufacturing processes to enrich understanding of potential sources of variability. Computational models for pharmaceutical processing have made significant advances in modeling powder mixing, spray drying, and tablet coating. The application of process analytical technology (PAT) has enabled heightened control of these unit operations and the ability to adjust for variations in material properties.  

What will be the influence of quality by design (QbD) on solid-dosage manufacturing in the years ahead? 

As the reviewers and inspectors for regulatory agencies begin to get more comfortable with the concept of design space, they will know how to rapidly review submissions and query the submitter directly about design space definition, robustness, and process capability of equipment. Ultimately, if the agencies can retain sufficient numbers of experienced personnel for review and inspection, the QbD process can hasten the decision process instead of being a barrier.  

The influence of QbD will eventually be enormous. Some companies already understand the potential benefits and are working towards it. Others will be forced into it by virtue of the questions FDA will raise if they do not include QbD elements in their new drug or abbreviated drug (NDA, ANDA) submission. QbD has the potential to improve the supply of drugs eventually. By definition, if we have undertaken our QbD development program properly and asked all the relevant questions, we should be developing more robust products. 

From its start, QbD has delivered more robust processes into the manufacturing environment. Regulatory and operational flexibility (i.e., the ability to make changes without regulatory action), however, have been difficult to achieve. We do see a shift in the approach towards reducing or eliminating the focus on design space and increasing the focus on control strategy. This opens the door to apply the tools of QbD to existing products where significant manufacturing experience can replace proactive developmental knowledge but achieve the same result of reduced variability of the end product. 

We have learned how to implement process parameter changes in routine manufacturing in order to optimize yield and robustness. As a global company, we are challenged by the fact that the QbD approach is not yet accepted in every country, and companies still have to run QbD and conventional filings in parallel. With time, this hopefully will change.  

Do you see solid-dosage manufacturing moving towards continuous processes?  

In the academic and private sectors, work is being done to understand, from first principles, the tablet manufacturing process and the methods needed to monitor and control the unit processes involved. Some companies have proven that real-time release can be a reality. The companies that comprehend the need to develop continuous, controllable processes for pharmaceutical manufacturing by using QbD and advanced control techniques will harvest the rewards that come from running capable processes that can be operated by far fewer personnel and turned around faster than in the past. Costly deviations and lost batches will become events of yesteryear, and the level of regulatory oversight for these companies will fall to a level that will allow the inspectorate to spend its time overseeing the companies that continue to follow paths of greater risk. 

I do think true continuous manufacturing—in which starting materials with predefined specifications are fed continuously and product is continually produced and removed from the process—is possible and can be achieved. Issues to be resolved include traceability in the event of a recall, contamination or adulteration of starting components, procedures for start-up and shut-down, and ways to deal with the inherent variability of the starting components. An interesting point is that many of the excipients used in the manufacture of pharmaceutical tablets and capsules are manufactured by true continuous manufacturing where the equipment is operated continuously 24 hours per day and seven days a week. These issues have been resolved for these materials, so why shouldn't they be resolvable for pharmaceutical tablets and capsules? 

Large-volume products can benefit significantly from the efficiency and throughput improvements delivered by continuous processes. However, at the current time, we are seeing a trend towards smaller volume products due, in part, to our focus on personalized medicines. One key to effective manufacture of small-volume products is the development of flexible modular manufacturing units that can be quickly assembled anywhere. These units will have some of the aspects of continuous processing (especially where it improves robustness), but will be more flexible for multiple small volume products.   

What may be the most significant advances of the next 5–10 years?  

As the QbD mantra rises in volume, the use of PAT will increase in order to acquire more molecular and process information earlier in the development process. PAT generates large volumes of data and can be implemented on most drug-product unit operations. The institutions and individuals capable of managing this mountain of information and turning it into knowledge will gain a competitive advantage by learning to bring molecules to the clinic faster and being prepared to manufacture the final drug product at a lower cost. In five years, this will be a common practice for perhaps 10% of the pharmaceutical industry. In 10 years, there will be new measurement techniques that will come to bear on every one of the solid-dosage unit operations. These measurements will provide new insight into powder formulation, powder handling, and powder compaction processes. This new knowledge will offer the committed manufacturer the opportunity to design more processes based on first principles and the confidence that they can reach the end in mind with a minimum of experimental work to validate their design.  

In the next five years, current research in API particle engineering will result in better control of API properties, enabling the use of simpler direct-compression processes for downstream drug-product processing. Within the next 10 years, the focus will be on technologies that improve efficiency in R&D and production. The development of flexible, modular manufacturing platforms for solid-dosage manufacturing will reduce the experimentation needed for technology transfer, getting drugs to market faster.   

The trend towards local manufacturing on a market-by-market basis is likely to drive demand for highly standardized, modular manufacturing units at medium-size scale and the flexibility to ensure manufacture of high quality product at any site with only limited operator input. Advanced process control will also play a bigger role. We will no longer just measure online intermediate and product attributes but will use feedback loops to optimize process parameters and product quality online. Ten years from now, the proportion of solid dosage forms will have decreased, and parenteral dosage forms of biotech products will play a bigger role. 

What would you identify as the most significant advances in parenteral manufacturing in the past 10 years?  

The single most important change in parenteral manufacturing has to be the maturation of isolation technology. Ten years ago there was still a lot of trepidation regarding isolators; it wasn't clear to the industry that expected operational advantages would overcome their added complexity. With the passage of time, we've better understood decontamination practices, defined realistic leak testing criteria, and most importantly gained sufficient operating experience. In addition, quantifiable cost benefits are now well documented, so perhaps the last hurdle to isolators increased adoption has now been cleared. We're starting to see the next generation of isolators emerge that provide even greater sophistication and performance. That wouldn't have been possible without the success we've witnessed in the last decade with this technology.  

Figure 2: Industry roundtable participants, from left to right: James Agalloco, president of Agalloco & Associates and a member of the Pharmaceutical Technology Editorial Advisory Board; Ryan Hawkins, vice-president and chief operating officer at Cook Pharmica; and Bernd Stauss, vice-president of production & engineering at Vetter.			

Decontamination cycles for barrier isolator technology are significantly shorter today. While cycles were 12–16 hours in the past, they are now 2–4 hours for equivalent isolator size. We also have conquered the learning curve of how to get things in and out of isolators and improved the ergonomics. We have met the goals of removing the risk of human contamination and having a validatable cleaning cycle. 

Automation has helped industry remove the need for human intervention. For example, it wasn't long ago that we manually fed nested syringe tubs onto the line and manually removed lids and liners, but today these steps are commonly fully automatic.  

Another advance of just the past few years is that use of disposables has gone from talk to action and is yielding significant savings in cleaning and time for set-up and tear-down.  

Continuous manufacturing: Solid-dosage manufacturing 			

The most important advance has been the increase in sterility in product manufacturing. New technology—such as isolators and restricted access barrier systems (RABS)—and conceptual approaches to manufacturing have significantly reduced the need for direct human contact with the product, thus reducing this key risk factor. Because of comprehensive automation in peripheral areas (e.g., transport and freeze dryer loading/unloading), manual interventions in aseptic production are kept to an absolute minimum. Automated cleanroom sanitization and the increased use of more complex disposable systems (e.g., filling pumps) contribute to reliable sterility. Fully automated visual inspection now allows for steady and high-level testing standards for millions of units. All combined, the continuing automation in parenteral manufacturing has allowed for a notable increase in quality and safety of drugs. 

Single-use disposables, which simplify set-up, cleaning, and system integrity, will become more prevalent. A gradual shift from glass to plastic containers will virtually eliminate breakage, avoid delamination and glass particles, reduce shipping costs, and lower utility costs, among other potential benefits. The next generation of filling equipment will operate in isolators with internal automation and robotics that will essentially eliminate the need for human intervention.  

Continuous manufacturing: Integrated API and solid-dosage manufacturing			

Further implementation of robotics technology will lead to advances in equipment. For example, prototypes exist today for lines that can run vials, syringes, or cartridges, rather than having separate lines for each. Ten years from now we expect to be using this type of combination line.  

From a supply chain standpoint, 10 years from now, companies will be more focused on where they can add value. For example, fill–finish lines will use ready-to-use vials rather than having vial washing at the start of the line. This is already occurring, but it will be several years before it really takes hold. We also expect to see more innovation in components and delivery systems, such as retractable needles and the blurring of the line between syringes and cartridges. While the benefits of plastic components compared to glass are documented, we see their higher cost as a significant barrier.   

An important task over the coming years will be to work in close cooperation with packaging suppliers to further align quality parameters in order to achieve higher quality levels throughout the entire supply chain. For example, using a laser in a cut-to-length process for the manufacture of glass barrels can meet increasing glass-breakage requirements. Another example is in the manufacture of components (e.g., stoppers), in which fully automated visual inspection can be used to check for defects (e.g., particles, inclusions).  

What do you think the influence of QbD will be in the upcoming years? 

The early adopters of QbD are well ahead of everyone else and making it evident there's much to be gained through it. Regulatory support, and certainly some prodding as well, is pushing the rest of industry to introduce it as a matter of routine. The benefits of QbD are well known, but it requires almost a cultural shift within the industry before it becomes standard practice. Once folks get comfortable with it, they won't want to develop any product or process without it.  

Regulatory authorities are clearly leading this effort, but like anything else, it takes time for everyone to understand how to implement it.  

Industry experts share their insight on solid-dosage and sterile manufacturing.

35th Anniversary Special: Breakthroughs and Emerging Technologies in Manufacturing

Development in hot-melt extrusion (HME) using twin-screw extruders to make solid-dosage drug forms has increased significantly in the past decade, although it is still in its infancy, said Charlie Martin, president of the US operations of Leistritz, at the recent Pharmaceutical Extrusion Seminar organized by the company. An interesting aspect of HME is the variety of physical forms that can be given to the melt after mixing.  

At Leistritz's processing lab, for example, seminar attendees observed demonstration lines producing cast film, tubing, and pellets. Films can be used for dosage forms such as dissolvable films or transdermal patches. Pellets can be filled in capsules, punched directly into tablets, or granulated for traditional tablet production. Foamed pellets for fast-acting dosage forms are a novel development. Extruded rods and fibers are also being used as a dosage form.  

Cutting extruded pharmaceutical formulations is often difficult because the polymers used are prone to fracture or smearing during pelletizing. Optimizing temperature and blade shape can help to solve cutting problems and minimize particulate generation, explained Bob Bessemer, sales manager for medical extrusion at the Conair Group, in his presentation. He noted that there are many technologies used in plastics extrusion that could potentially be applied to pharmaceutical extrusion. In wood-plastics composite processing, for example, extra sections are added to the end of the extruder to control cooling and thus improve cutting. He predicts that someday pharma manufacturers will be able to cut extrudate directly into tablets, once the problems of cutting and swelling are solved. 

Borrowing another common plastics processing technique, tablets could also be directly injection molded after extrusion, noted other presenters. Looking to the expertise of the plastics industry may help propel development of pharmaceutical extrusion.  

Developments in hot-melt extrusion using twin-screw extruders to make solid-dosage drug forms.

Hot-Melt Developments

The U.S. District Court for the Southern District of New York found in favor of Teva Pharmaceuticals in the company’s patent-infringement lawsuit against Momenta Pharmaceuticals/Sandoz and Mylan Laboratories/Natco Pharmaceuticals regarding Teva’s relapsing-remitting multiple sclerosis (RRMS) product, Copaxone, the company said in a 

.  The suit included infringement of multiple patents covering the chemical composition of Copaxone, methods of using the product, and processes for manufacturing the product.  The defendants had claimed that the patents were invalid and unenforceable, but the judge rejected this claim and ruled that the generic versions of Copaxone infringe upon Teva’s patents. This ruling should prevent FDA approval of generic versions in the US at least until the Orange Book patents expire on May 24, 2012. Teva believes the decision will further prevent the sale of generics until the process patent expires on September 1, 2015. 

Mylan expressed its disappointment in the decision.  “While we have not yet had the opportunity to review the Court's opinion, we fully intend to evaluate our options for an appeal once the Court's full opinion becomes available,” stated Heather Bresch, CEO of Mylan, in a 

.   Mylan’s earnings guidance for 2012 and earnings targets for 2013 remain unchanged because they were not reliant on the launch of a generic Copaxone, Bresch added.  In 2008, Mylan had signed an agreement to license and supply India’s Natco Pharma’s glatiramer acetate prefilled syringes, a generic version of Copaxone. 

Momenta, which had partnered with Sandoz, a division of Novartis, also stated its intention to appeal the decision. "We are disappointed that the court determined that Teva's patents were valid and infringed, and we look forward to reading the full opinion to understand its reasoning," commented Craig Wheeler, president and chief executive officer of Momenta in a

.  "We remain confident in our legal position and we intend to appeal." 

US court ruled in favor of Teva in its patent-infringement lawsuit against Momenta and Mylan's generic versions of Teva's Copaxone.

Teva Wins Patent-infringement Lawsuit Protecting Copaxone

	Development in hot melt extrusion (HME) using twin-screw extruders to make solid-dosage drug forms has increased significantly in the past decade, although it is still in its infancy, said Charlie Martin, president of the US operations of Leistritz at the recent 

 organized by the company. An interesting aspect of HME is the variety of physical forms that can be given to the melt after mixing.

	At Leistritz’s processing lab, for example, seminar attendees observed demonstration lines producing cast film, tubing, and pellets. Films can be used for dosage forms such as dissolvable films or transdermal patches. Pellets can be filled in capsules, punched directly into tablets, or granulated for traditional tablet production. Foamed pellets for fast-acting dosage forms are a novel development. Extruded rods and fibers are also being used as a dosage form.

	Cutting extruded pharmaceutical formulations is often difficult because the polymers used are prone to fracture or smearing during pelletizing. Optimizing temperature and blade shape can help to solve cutting problems and minimize particulate generation, explained Bob Bessemer, sales manager for medical extrusion at the Conair Group, in his presentation. He noted that there are many technologies used in plastics extrusion that could potentially be applied to pharmaceutical extrusion. In wood-plastics composite processing, for example, extra sections are added to the end of the extruder to control cooling and thus improve cutting. He predicts that someday pharma manufacturers will be able to cut extrudate directly into tablets, once the problems of cutting and swelling are solved.

	Borrowing another common plastics processing technique, tablets could also be directly injection molded after extrusion, noted other presenters. Looking to the expertise of the plastics industry may help propel development of pharmaceutical extrusion.

Development in hot melt extrusion (HME) using twin-screw extruders to make solid-dosage drug forms has increased significantly in the past decade, although it is still in its infancy, said Charlie Martin, president of the US operations of Leistritz at the recent Pharmaceutical Extrusion Seminar organized by the company.