The 2007 Team of the Year Finalists

One of the processes used by QA to speed batch production was FIFO (first in, first out), which meant working on batches in the order in which they were received. This process gave direction to the Quality personnel working on the releases. While QA is essential to GMPs, it is often considered a “paper factory,” according to Kakkar. The capacity of the process is tied to the batch release.

Process improvements have significantly enhanced performance in quality and compliance, cost and waste reduction, and customer service and responsiveness. The plant has realized a more than 65% reduction in production and release cycle time since January 2006 to June 2007. The team also released 79% of batches (using May 2007 data) the same day sterility results were made available.

“You improve cycle time by having good quality measures,” states Alex Tosi, manager of operational excellence and strategy. However, quality improvements are hard to measure. “Measure [was the hardest part of the DMAIC process to implement] because the data are not readily available,” Tosi explains. “We needed to design the process.”

The improved performance for the supply-constrained process actually caused the site’s materials planning director to constantly have to “apologize” for exceeding the supply plan from a yield and timing standpoint. The process cycling time has since been reduced to match the production plan.

“We know these improvements are working because we are about two times faster at producing and releasing our product than a third-party manufacturer who makes the same product [for us],” says Tosi.

Motivational Momentum

As the team began to see the improvements exceeding their initial expectations, they became motivated to do more. Three yield improvement projects in the filling, inspection and packaging areas reduced product waste, translating to a cost savings of almost $5 million a year. Tosi notes that the site’s fill-finish output per batch is 11% higher than its third-party manufacturer’s output.

“We use metrics and keep our deliverables and measurables on the dashboards,” says Kakkar. “It is an ongoing process, and this is where the improvement becomes real.”

Product variability also has decreased for the top 90% of the team’s releases. According to Tosi, they have not only driven down the average cycle time, but also reduced the variability between the high and low values to ensure a more predictable and reliable product supply of this life-saving vaccine (Prevnar, which protects infants and children from diseases caused by Streptococcus pneumoniae). The combined efforts resulted in 99.9% product availability in 2006.

Deviations per batch also have gone down by 25% since the beginning of this year. “As we further optimize the process using Quality by Design, we are making more measurable gains,” says Kakkar.

One of the key transformations enabling this improved performance has been increased partnering from all the disciplines at the plant, such as Operations, QA, QC, Maintenance, Materials Planning and Training. According to Lynn Bottone, senior director, fill-finish PPU, factory leaders have championed an important cultural shift in thinking from “quality AND operations” to “quality IN operations.” In addition, Kakkar explains, deviations are now dealt with immediately. “We bring QA, Operations or whoever else is needed into the conversation right away,” she says.

The remarkable part of these projects is that they were carried out during a period of time when production output increased by approximately 100%. One factor in this success was that the packaging line area reduced equipment downtime by 15%. Increased demand projections were met without the need to add capacity or extensive overtime.

Not Just for Manufacturing

As a result of all these projects, one team member became certified as a Lean Six Sigma Black Belt and another candidate is pursuing certification. In addition, two team members have received Green Belts and several more are close to certification.

These projects demonstrated that any operation can benefit from a Lean Six Sigma DMAIC process. “You don’t need to be a manufacturing operation in order to implement these principles,” says Bottone. “This was a quality group achieving this success.”

FDA-Conformia QbD Workshop Team

Breaking the FDA/Industry Impasse

Collaboration between the Agency and a software provider, using data from select manufacturers, is paving the way for positive change throughout the drug industry.

This team has been in existence since FDA and Conformia launched a joint Cooperative Research and Development Agreement (CRADA) in 2005 to study roadblocks to reaching the “desired state” of science-based drug development, manufacturing or regulation. Initial research efforts focused on practices at nine pharmaceutical companies that agreed to be studied as long as results were blinded.

Several seminars were held, but there was still a lack of dialogue between cross-functional industry leadership — the heads of development, quality, regulatory and manufacturing — and among different groups within FDA (policy, reviewers and inspectors).

Guided by results of the original CRADA study, the team collaborated on a series of workshops that would address the challenges that pharmaceutical companies and FDA face in clarifying Quality by Design.

As team member Helen Winkle, director of CDER’s Office of Pharmaceutical Sciences, has noted, the benefits of implementing QbD are potentially great for both industry and FDA. They include:

1. Reducing the number of manufacturing supplements required for post-market changes
2. Designing better product with fewer problems in manufacturing
3. Allowing for implementation of new technology to improve manufacturing
4. Possibly reducing the overall costs of manufacturing, and eliminating waste
5. Reducing hassle during review and deficiencies
6. Improving industry interaction with FDA, so that communications are focused on science rather than on process
7. Allowing for continuous improvement in products
8. Improving understanding of how APIs and excipients affect manufacturing
9. Relating manufacturing to clinical during process design
10. Improving the overall business model.

The goal of these workshops was communication in which clarification from industry and from FDA could be sought and key challenges and obstacles could be discussed. The workshop also utilized a mock section of a drug application created by the European Federation of Pharmaceutical Industries and Associations (EFPIA) as an example of an ICH Q8 P2 (a Pharmaceutical Development quality guideline issued by the International Conference on Harmonization), using the QbD paradigm.

The workshops enabled critical interaction between cross-leadership teams, involving not only the regulatory department, but also development, manufacturing, information management and quality. They also engaged senior management by advancing high-level cross-functional management support through QbD case study problem solving.

The first pilot workshop was held in July 2006 with Johnson and Johnson, Lilly and Amgen attending. Since then, three more workshops have been held, with another one set for this month. PhRMA joined as a collaborator and plans are under way for the entire pharmaceutical industry to participate and for a new case study to be created.

Noting that there were differing opinions on how management views FDA and its commitment to QbD, Kataria says that dialogue at these meetings has helped create an exchange of confidence among participants and FDA.

Workshops focus on case study problem-solving, which has helped participating team leaders better resolve issues and galvanize their teams. The program has also addressed the perceived “disconnect” between reviewers, inspectors and policy groups within FDA.

The partnership has already begun to give participants on both sides a clear, realistic picture of what pharmaceutical companies go through in developing new drugs, and to educate regulators on these realities so they can better understand how to apply guidance, particularly the new set of directives in ICH Q8 and Q9. Clarifying the terminology in Q8 and Q9 will lead to more effective filings that demonstrate process understanding, prior knowledge, risk management, control strategies and knowledge of the design space.

The FDA-Conformia CRADA team offers a model of how private and public sectors can work together effectively to solve important problems. The overall impact of implementing the concepts of ICH Q8 and Q9 will be felt by every person that takes a drug product, because these guidelines are helping companies to build quality into the process and ensure higher safety and quality of products throughout the pipeline. These approaches can also help bring new drugs to market faster; if companies can demonstrate these principles in the filings, the Agency is more likely to give regulatory relief.

From FDA’s perspective, Helen Winkle says the workshops and the CRADA overall have gathered useful data from which FDA can determine strategies.

“The four joint workshops and training sessions have been among the very best I’ve ever attended,” Winkle remarks.” Open, frank interactions between the Agency and industry representatives, especially in a crossfunctional framework, have been helpful in proposing resolutions to current issues.”

Such efforts will be critical to future success, Winkle suggests. “QbD is the wave of the future and more pharma companies (and FDA staffers) need to jump on board,” she says. “The more companies we have, the better and the more information we can share.” The key, she indicates, will be to establish a true dialogue, and the training sessions have already begun to lay a foundation for that dialogue.

Luitpold Pharmaceuticals’ Microbiology Team

Modernizing QA Microbial Testing

A generic drug manufacturer’s microbiology team developed testing methods that improved control and reduced cycle times.

The traditional microbiological testing required for Quality Control (USP testing: LAL Bacterial Endotoxin Testing, Sterility Testing, Microbial Limits Test, Microbial Identifications, Environmental Monitoring Program, Disinfectant Efficacy Testing, Various Validation Projects) are also tests of operators’ patience. For some standard procedures, it can take weeks to get results.

However, at Long Island, N.Y.-based generics manufacturer Luitpold Pharmaceuticals, a dedicated team pursued different approaches, only to find that their efforts to streamline lab testing, sample analysis and environmental testing improved productivity and morale, adding substantially to the company’s bottom line.

“We’re always looking for ways to increase effectiveness and efficiency in the laboratory,” says department supervisor Rich Boehler. To some, that statement might suggest tweaking processes or finding new suppliers, but this team aimed significantly higher.

Senior biologist Tom Cadolino developed methods using UV spectrometry and microscopic analysis that improved accuracy and reproducibility by 20%, reducing from weeks to hours the time required for environmental microbial monitoring. The team also implemented a new method for endotoxin testing, moving from traditional gel clot tests to kinetic turbometric processes, according to department manager Susan Klein.

Developing the spectrophotometric method took more than a year. “The effort is ongoing because the method is very species-specific,” Klein explains. “We’re still working on it, as well as the kinetic turbometric technique.”

Cadolino also developed a new alternative to plate counts, as a way to enumerate bacteria. The company has submitted an abstract on the method to USP. It took three to six months to write the reports — the Installation Qualification, Operational Qualification and Performance Qualification — and get it up and running, according to Klein. Now, however, this method is being used to test 70% of Luitpold’s parenteral product line.

Another of the team’s accomplishments was establishing a technique to optimize sampling for environmental conditions. Klein says this new technique, for which the team just submitted a paper to the Parenteral Drug Association, would reduce sampling time for environmental monitoring from one week to three days and allow the work to be done at one temperature, rather than the two that are traditionally required.

Implementing these new methods was a challenge, as this work complemented an already hectic product release schedule. “We are 10 people here and we work very hard,” Klein says. However, the investment paid off, as USP has approved, or at least not prevented, use of these new methods for microbiological testing. FDA approval was not required.

As a result of all these initiatives, the Luitpold team has gained control over the testing process, reduced cycle times and enhanced customer service. Conquering these challenges has also improved team morale. Between that and the ease with which the team gained management buy-in for these projects, Cadolino indicates that the team is setting its sights on developing more new methodologies in the future.

Wyeth Consumer Healthcare Enhanced Due Diligence Team

Bigger Isn’t Necessarily Better

The evaluation of new contract manufacturing opportunities requires a quick, clear and consistent process. In 2005, the ad hoc Due Diligence (DD) team at Wyeth Consumer Healthcare External Supply did not fit the bill. The team seemed separate and cumbersome, with no clear understanding of or accountability for the required outcome. Frustration with the process sparked a change.

A cross-functional team sponsored by the Leadership Team set out to fix the many problems, identified as:

• Excessive number of personnel assigned to attend (~12)
• Lack of accountability
• Diffusion of responsibility
• Inconsistent output in terms of report writing: content, timing of issuance and usefulness in decision making
• Separate visits by due diligence and global compliance auditing teams to the site with contradictory findings
• Extensive time lapsed between DD initiation and decision making due to a weak, prolonged process.

“The ad hoc Due Diligence team just wasn’t working,” says Steve Hamilton, senior director of technology, external supply. “We didn’t have a consistent approach. We knew there had to be a better way that would result in a better predictor for success.”

The team was reorganized. A new core team of four (consisting of members from global strategic sourcing, technology, quality and compliance) engaged other departments while developing tools to improve the due diligence execution process. These tools have since been incorporated into standard operating procedures.

According to Hamilton, the size of the previous group was a stumbling block. “Once, [the ad hoc team] showed up at a site visit with 13 people, and the entire plant we were examining only had 74 people,” he recalls. “Our roles and responsibilities were unclear.”

One of the keys to the new process and a factor that helped reduce the group’s size was improved preparation. Prior to a site visit, enhanced checklists are sent that highlight the potential contractor’s business information, health and safety data and good manufacturing practices. These forms are completed before the visit and enable the Qualification team to identify risk areas quickly and develop a strategy for the visit.

“These standardized questions spot potential issues that we can focus on during the due diligence visit,” says Hamilton. “For example, if it is an NDA (New Drug Application) product and the contractor has no experience, it doesn’t rule them out — it just gives us specific areas to spotlight when we are there.”

These checklists reduce the planning time for a more comprehensive site evaluation and are coordinated with the compliance auditing teams, ensuring that critical areas are thoroughly covered between the participants — but only once. Therefore, the due diligence strategy is tailored to each contractor.

The plan allows the due diligence visit and global compliance audit to be accomplished in a single visit over two consecutive days instead of two or more visits taking three to five days. Typically, a site tour now involves only four people, which accelerates the trip and the report writing process. Individual team members are now more accountable for the results of the due diligence process.

Reports and Decisions

The team also improved the formatting of its reports, so that findings are clearly broken out by quality systems, commercial issues, development issues and conclusions. The reports can be scanned for key issues or topics of particular interest to the reader or the project.

“Previous reports focused on functional areas and didn’t match up with the findings from other areas. They were disjointed,” says Hamilton.

A report template ensures consistency in the content and expedites the writing process. Each team member drafts content for his/her own areas of evaluation, which are merged into the final report. Generally, reports are finished about 10 days after the visit, compared with up to 60 days previously. The coordinated strategy and single site visit enhances the collaboration among the team members. In addition, a common perspective is often reached regarding the contractor’s viability. Previously, different functional groups would sometimes have differing opinions on the project.

“The reports are now more comprehensive and describe the pros and cons of the prospective contractor,” says Hamilton. “The path forward is clear from the reports.”

As a result, decision-making is more timely. For example, Hamilton says, quick site selection was crucial during a recent project to decide whether a product should be launched at the contractor’s site or at a Wyeth site. A decision was made within seven days. An alternate cough drop supplier project achieved consensus within three working days.

“The reports clearly lay out the capacity and cultural issues of a site. The key is that the report is data-driven and consistent between different site visits,” says Hamilton.

The value of this process has been recognized outside of External Supply. The process and the checklists were used to evaluate a potential corporate purchase. The tools enabled diverse manufacturing sites located in different countries to be evaluated in a four-hour timeframe. Over 15 Wyeth personnel were able to use the checklists with little or no training. In addition, Wyeth’s EU External Supply team piloted the process and incorporated valuable feedback, which validated the process.

The new process did require a cultural change at Wyeth. Different groups were no longer going on due diligence trips. This was met with some resistance. Further, even with the new process, differences of opinion sometimes lead to contention during decision making.

“Not everyone on the team may like the final decision, but [decisions] are now data-driven,” says Hamilton. The process is formalized, and there is no second-guessing.”

Wyeth Consumer Healthcare External Supply Project ICE Team

Collaboration Prevents a Headache

By analyzing communication, raw material procurement and manufacturing steps in conjunction with a contractor, this team reaped a multitude of benefits.

Quality and availability are two of the key ingredients in drug manufacturing. Faced with a constrained output, Wyeth Consumer Healthcare’s requirements from Contractor C were not being filled. The product also was experiencing sticking, clumping, dragging and tension. Something had to be done.

However, this was not just any old product – it was Advil Liqui-Gels, one of Wyeth’s flagship brands – and the contractor is one of the company’s biggest. Both firms realized that success was possible, but only through a collaboration focused on improving both quality and quantity. “Project Innovative Contractor Execution” (ICE) was launched.

“We began looking at another location for production of this product, but we realized how important this collaboration was,” says Jane Wong, director of compliance for Wyeth Consumer Healthcare External Supply. “That other site is now used as a backup.”

The partnership was designed to improve the cycle time at all stages of the process: ordering, scheduling, manufacturing, testing, disposition and delivery. The core group included nine Wyeth personnel and nine staff members from the contractor.

“The contractor saw this as an opportunity and had a vested interest in improving their delivery. They couldn’t produce as much product as we needed but were willing to cooperate with us to do what it took,” says Brian Bennett, director of external operations.

Reducing Cycle Time

Wyeth technology personnel worked with the contractor and provided technical expertise in identifying cycle-time reduction opportunities and helping to achieve them. These projects included:

• Drying Tunnel Modification – Increased the drying capacity by improving and standardizing the process. Modified the air flow on the drying alleys (ventilation systems, register, removed return ducts, balanced air flow) to make the flow equivalent to the other side, already in use. This increased drying capacity by 73%.
• Manufacturing Step Decrease – Redesigned the process down to a single step, resulting in greater uniformity, predictability and efficiency and less staging time, which in turn decreased cycle time.
• Microbial Testing – Reduced cycle time by two to three days by eliminating the microbial specification.
• Product Wash – Replaced a wash using naphtha with denatured ethanol/phosal. This eliminated a bricking/clumping problem and reduced drying time.

“Eliminating the microbial testing specification was a key step,” says Bennett. “We researched the situation, put a package together and presented the facts. This was a low-risk opportunity.” This approach for justifying microbial specification elimination is now being applied throughout Wyeth to other contract-manufactured products, where applicable.

Capacity also was increased through a series of projects. Wyeth modified its trays to accommodate more trays per stack. This resulted in a 44% increase in capacity. These trays can also be used for other products, but would have to be verified first.

Identifying the drying process as a bottleneck, the contractor installed a mega-tunnel for drying all Liqui- Gel products. This increased capacity by 33%. Still under way is a project that speeds up the line, reducing the encapsulation cycle time from three days to two.

Enhancing Communication

The ICE team worked with the contractor to streamline and optimize the communication channels and reporting requirements between the two companies. Value stream mapping was used to analyze the interaction between Wyeth and the contractor. The process identified information needs, eliminated redundant or unnecessary reports, and instituted a system-generated methodology where possible.

“We started by looking outside the box at the interaction between the companies,” says Bennett. “By streamlining the process, we could not help but find ways to improve the process inside the box.” The results included reductions in the number of reports, total pages and man-hours needed to generate the reports.

A direct outcome of the mapping process was the establishment of an e-room. This common area is used to centralize master schedules and documents between Wyeth and the contractor. “This contractor runs over 140 batches a month for us – that is a lot of paperwork,” Bennett points out. “This common area speeds the document process and prevents misplacements.”

A kanban (just-in-time) initiative was requested by the contractor to simplify the procurement process for one of the lines. Through the kanban system, Wyeth places a blanket purchase order annually to the raw material supplier. The contractor communicates directly with this supplier when its kanban system triggers a shipment. This process reduces the P.O. maintenance transactions performed by Wyeth and allows the contractor to communicate directly with the raw material supplier regarding delivery dates and quantities.

“These kinds of collaborative approaches are based on trust and solidify your relationship,” says Bennett.

Such enhancements have reduced the production cycle time by 50%. In addition, capacity output has increased by 33% (2006 vs. 2007). Report processing time was reduced by 62% through customization. In all, 18 different projects were accomplished at three locations.

“You can’t work on everything at one time. We prioritized and picked the lowest hanging fruit first,” Bennett explains. “By collaborating, we got remarkable results.”

The partnership approach is being extended to additional Wyeth contractors. A collaboration with another contractor started in March; it includes 10 different disciplines and 16 different projects.

“Partnering for improvement works,” Bennett observes. “It takes patience, perseverance and commitment, but the benefits can be phenomenal.”