Isolator approach to parenteral manufacturing

As bio-pharm manufacturers continue waging war against microcamination in their critical processes, isolator technology emerges as a leading trend in providing for safely, cost-effectively satisfying the needs of an expanding global marketplace.

Continually evolving regulatory standards and unacceptable GMP and financial risks to owners– coupled with vastly improved alternative technologies– make traditional aseptic clean rooms a non-viable option for optimizing manufacturing process and potent product purity.

RABS facilities are rapidly losing favor due to increasing regulatory restrictions on their use, questions relating to cleaning technology, and escalating costs.

In addition to being viewed as a preferred option by the USFDA, isolator-based facilities offer more advanced technology, improved economic and life cycle advantages and quicker product speed-to-market than other alternatives.

Isolating parenteral filling operations
Designing isolated processing capabilities for parenteral manufacturing requires operators to first clearly define key factors such as ISO air classification, personnel gowning and operating layout methodology.

Room classifications– A properly designed isolator environment enables all filler and lyo loading/unloading and capping operations for potent products to be performed under Grade A/ISO 5 conditions to minimize contamination from non-viable particulate. Other critical areas requiring unidirectional Grade A/ISO5 air supply include areas around open ports to formulation tanks, bag wrapping area after parts washer, exits to autoclaves and other connections between the formulation tank and filling line.

Based on USFDA minimum class 100,000 air requirements, the remainder of the parenteral manufacturing suite shall be classified Grade C/ISO 8. These spaces include the filling room, formulation room, clean equipment and tank storage areas, pre-wash room, wrapping room, sterilized parts staging areas, tank wash, cleaning solution prep and pharmacy.

Gowning– Specific personal hygiene techniques vary according to company philosophy, but typically require operators to wear a one-piece suit gathered at the wrists and ankles, along with shoe covers before accessing a Grade C/ISO 8 suites.

Facility layout options– Production alternatives vary according to a specific manufacturer’s product and logistic requirements.

• GMP Corridor– This approach is based on transition ports entering a common GMP corridor with access all processing areas; all rooms maintain the same air classification with positive pressure differential to adjacent spaces. This design works well in processing potent compounds and provides local containment of spills. The downside is that it requires about ten percent more space than alternative options, and traversing additional doors sacrifices some efficiency.
• Ball room– The most efficient design for fully segregated/dedicated high volume multiple non-potent product suites, allowing transition ports and all processing rooms to be accessed from the filling room. Same air classification applies to the entire cell, with positive pressure differential between filling room, formulation room, wash rooms and transition ports.
• Parallel filling– Essentially a variation of the GMP corridor concept, this utilizes multiple (parallel) filling lines with dedicated formulation rooms and shared support functions. Ideal for large multi-line facilities, it provides uniform unidirectional material flow and product segregation while eliminating cross-contamination.
• Multiple delivery systems– A variation of the parallel filling design, can be housed in the same facility utilizing a Grade C/ISO 8 classification. Isolated liquid and lyo vials, pre-filled bulk and nested syringes, form/fill/seal (FFS), non-isolated blow/fill/seal (BFS) and non-isolated terminally sterilized vials are placed in adjacent filling suites. Although BFS rooms are designated Class C/ISO 5, operators must be gowned for Class A/ISO 5 in the “white” side.
• Add-on isolators– Facilitate updating isolated filling opportunity utilizing existing parenteral facilities that may have adequate Grade C support functions but outdated Grade A/B ISO 5 capabilities. Extremely economical and compliant, this approach enables placement of isolated filling lines in vacated spaces, while allowing the manufacturer to leverage existing support functions.

Finishes and fixtures
To ensure optimum cleanliness, all wall, floor, ceiling and work surfaces must be monolithic, smooth and durable enough to withstand rigorous cleaning. Also coved corners should be incorporated, where applicable. Chemically welded, prefabricated aluminum modular panels are preferred over stick built drywall construction because of their durability, flush detailing of doors and windows and limited use of calking.

Even color choice can play an important role in helping assure cleanliness in an isolator facility. Isolator facility designers have found a combination of blue and blue-based white to be most compatible with aseptic applications.

Global acceptance
Isolation technology has been successfully implemented by some of the world’s leading biotechnology and pharmaceutical manufacturers in plants throughout the U.S., Puerto Rico, Europe, India and China.

Global warming and the pharmaceutical industry

Global Warming and the Pharmaceutical Industry
Global Warming and the Pharmaceutical Industry
You don‘t have look to hard to see the impact of higher energy costs. Nearly every thing we consume is affected by higher energy costs. In fact, the global demand for energy continues to grow at a rate far above our current production capacity and this differential has resulted in a diminished supply of resources and a spike in energy prices that is not likely to change anytime soon.

The relationship between CO2 emissions, energy consumption and Global Warming has been well documented. Did you know that in a recent survey by McKinsey, 60% of global executives regarded climate change as strategically important, and the majority considered it important in product development? Designed to raise awareness and identify current trends in corporate governance, research studies like the McKinsey Global Survey and the Carbon Disclosure Project report how executives plan to deal with social and environmental issues such as global warming, greenhouse emissions and energy usage within their companies. To-date, findings have been mixed but encouraging as corporations are taking responsibility for the impact they have on the environment.

Most Fortune 500 decision-makers surveyed readily acknowledge the need for structured climate change initiatives as part of their overall business strategy– many even view it favorably from a profitability standpoint. But almost half of those surveyed noted that it is currently not a significant item on their agenda. Part of the problem may lie in how capital is allocated in some businesses, forcing management to focus more on the first cost of a venture than the less obvious long-term life cycle costs. But within buildings, especially pharmaceutical manufacturing facilities– complex entities that for the most part are designed and built by a fragmented supply chain which must be designed and operated to conform to strict regulatory requirements in a effort to ensure the quality and efficacy of their products. There are barriers and a reluctance to try something new in the event that it could compromise the product. With cost of goods driving the Pharma business, innovative companies are beginning to take a risk-based approach to operations and look for ways to conserve energy and reduce costs.

Buildings and the built environment are at the epicenter of energy consumption and green house gas emissions. Energy consumed by a building over its 40 to 50 year lifecycle vastly exceeds the amount energy required to manufacture and construct it. In fact, in a typical building, energy is the single, most controllable operating cost representing on average 30 percent the buildings total costs. Once you start thinking in terms of the building lifecycle, it‘s easy to recognize the indisputable importance of optimizing energy performance during the design phase and as part of daily operations for existing structures. There are many things that can be done to reduce the energy footprint of a building. Designing and operating to measurable standards such as the US Green Building Council‘s LEED Standards, the DOE and EPA sponsored Laboratories for the 21st Century (Lab 21) Standards and the EPA‘s Energy Star Program to name a few. Another opportunity to reduce energy consumption in the built environment is commissioning and retrocommissioning. Studies have shown that buildings that have been commissioned, on average save more than 5% compared to building that have not been commissioned.

Supply Chain
Drug producers and other process manufacturers must rely on continuous availability of affordable energy, along with essential raw materials, utilities, labor and other resources needed for product development and manufacturing. The complete cycle from raw material to finished product represents the supply chain. Each of the components used in the manufacture of finished goods consume resources and so they too have an impact on the on the total energy and carbon footprint. Many companies are looking at their impact on the environment by measuring what they consume in terms of demand side management. However, few are looking at all components consumed in their operations for impact on the environment. Some examples might be the use of recycled material for packaging, the redesign of packaging materials to minimize the environmental impact, sourcing local products to eliminate transportation impact. Looking at lean and green manufacturing techniques to reduce waste, environmental management, plant location, procurement and waste management should all be factored into the comprehensive strategic decision-making process.

Regulations
Historically the US government has been reluctant to establish greenhouse gas emissions limits. However, recently a coalition of states has taken matters into their own hands by establishing limits and setting up market mechanisms, such as cap-and-trade programs, to reward polluters for cutting emissions. Some plans will even work with Canadian provinces. Known as the Regional Greenhouse Gas Initiative (RGGI) and formed in 2005, and signed by 10 states in the East (Connecticut, Delaware, Maine, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, and Vermont) the group set mandatory emissions caps of carbon dioxide at power plants and allows sources to trade emissions allowances. The program becomes active in 2009 by capping emissions near current levels and then reducing emissions 10 percent by 2019. The Western Climate Initiative was formed in early 2007 and was signed by seven states (Arizona, California, Montana, New Mexico, Oregon, Utah, Washington and provinces of British Columbia and Manitoba). This program covers the main greenhouse gases including carbon dioxide, methane and others and sets economy-wide greenhouse gas emissions target of 15 percent below 2005 levels by 2020, or approximately 33 percent below business-as-usual levels. Members agreed to set a regional emissions target and establish by August 2008, a market-based system such as a cap-and-trade program covering multiple economic sectors. The Midwestern Regional Greenhouse Gas Reduction Accord was formed in late 2007 by six states and one Canadian province (Illinois, Iowa, Kansas, Michigan, Minnesota, Wisconsin, as well as Manitoba). Members agreed to establish regional greenhouse gas reduction targets, including a long-term target of 60 to 80 percent below current emissions levels, and develop a multi-sector cap-and-trade system to help meet the targets.

Converting plans into actions
According to the United Nations Environmental Program (Sustainable Construction & Building Initiatives) buildings represent from 30 to 40 percent of all global energy consumption. And significant gains can be achieved to combat global warming by reducing energy use and improving building efficiency. This requires coordination of appropriate regulatory oversight, behavioral change and increased focus on energy-saving technologies to substantially reduce carbon dioxide (CO2) and other harmful emissions. For the Pharmaceutical Industry, it also means performing a risk assessment to identify where there are opportunities to conserve energy without compromising product.

Included among the many steps corporate executives and building owners can take right now to put action behind this a new way of thinking are:

• Forming a Sustainable Task Force to look at operations
• Develop a formal position on Sustainability
• Develop a plan to design, build, and operate sustainable facilities
• Establishing CO2, emissions and energy conservation goals on a corporate-wide basis
• Consider offsetting corporate carbon footprint by purchasing Renewable Energy Credits (RECs), Energy Efficiency Credits (EECs) or other tradable credits in the carbon market
• Conducting a life cycle analysis to accurately assess long-term financial impact of energy conservation and environmental strategies

Many corporate leaders and stakeholders, once concerned over the costs of responsibly managing climate change, are now discovering the advantages of building and operating sustainable facilities to effectively reduce emissions and energy usage. Included among the many dividends is what is known as the triple bottom line (Economic, Environmental and Social).

Build new...or upgrade?

That’s the dilemma facing many bio-pharm companies looking to broaden their manufacturing capabilities to meet ever-changing strategic goals.

Growing market demands may favor expansion, which traditionally has meant new plant construction. But current economic uncertainty coupled with high energy costs, is raising a red flag among corporate financial managers who caution against assuming additional capital risk exposure.

As a result, many drug producers are opting to upgrade existing plant facilities to accommodate new product and manufacturing technologies, increase containment levels, and facilitate handling of flammable solvents required for certain types of chromatography operations. Along with this, operators are striving to improve product throughput and speed-to-market through process debottlenecking initiatives designed to enhance clean utility capacity such as water or clean-in-place (CIP) systems.

Another key driver of this trend is the recent increase in bioreactor production, especially as relating to monoclonal antibody products. Innovations in bioreactor operations, especially controlled nutrient and advanced cell line development are helping to provide much higher product yields.

Downstream operating capacity and support functions, such as buffer prep, must likewise be increased to improve manufacturing throughput. To achieve that, manufacturers are employing large-scale usage of in-line dilution of concentrated buffer solutions to supply increased buffer capacity while minimizing the need for large equipment.

Underscoring the challenge that confronts the biopharm industry to optimize its plant efficiency and product market life, several international drug producers are designing and building facilities to manufacture biosimilars (biogenerics).

Many facilities constructed in recent years already incorporate the basic capabilities needed to adopt future technologies, support multi-product operations and meet international regulatory compliance. Although some now employ single-use technology, with the right process engineering expertise they can be easily reconfigured for new product and manufacturing processes.

Modification of existing facilities to produce second generation products is a prudent alternative to improve product speed-to-market and maximize economic return on assets. As a recognized leader in developing projects for the biotechnology industry, IPS has extensive expertise in this type of project application and provides economic and flexible solutions that improve manufacturing utilization.

Teaming up for innovative solutions

How does a pharmaceutical leader like Bristol-Myers Squibb (BMS) deliver viable solutions to help meet the challenges of Alzheimer’s, diabetes, hepatitis, HIV/AIDS, cancer and many of society’s other clinical needs?

One way is by keeping pace with the highest standards of manufacturing technology to support its product development pipeline. Most recently, this was reinforced by a facilities redesign initiative to combine early and late phase cGMP clinical manufacturing and development scale-up at the company’s new Pharmaceutical Development Center of Excellence R&D site in New Brunswick, New Jersey.

As part of that evolution, BMS launched its Clinical Supplies Manufacturing and Drug Product Technology Expansion Project, earning it the 2008 ISPE, Interphex, Pharmaceutical Processing Facility of the Year Award (FOYA) for Equipment Innovation.

Dual–phased approach
The BMS team of corporate and third-party planning, design and construction specialists followed a phased approach to the project, with a goal of creating a flexible facility for multi-product clinical scale manufacturing and processing of solvent–based and potent compound products.

Under Phase I, a 93,000 square foot Clinical Supply Operations (CSO) facility was created to support three key manufacturing functions: a parenteral area equipped with an isolated vial filling line to satisfy sterility and containment requirements; a second zone dedicated to handling OSD products within Active Pharmaceutical Ingredients (API) bands one through four; and a third facility for OSD band five drugs.

In addition, to help ensure product integrity and operator safety, the facility supports full containment for expanded Oral Solid Dose (OSD) operations, incorporating what has been described as the most flexible continuous barrier line in the United States. The new CSO complex is capable of processing oral solid dose batches of up to 400 kilograms and parenteral liquid-fill batches of up to 250 liters.

Phase II of the BMS project called for approximately 39,000 square feet of expanded capabilities to supplement existing OSD operations, and housed a new stand-alone Product Technology Center (PTC) for product development and scale-up. Typical PTC batch sizes can range from 20 kilograms to 100 kilograms. This facility is also designed to handle API band one through four operations.

Expanded oral solid dose operations allow BMS to manufacture Long Term Stability batches to aid in product scale-up and technical transfer to commercial manufacturing sites with batch sizes at least one-tenth of commercial scale.

The Product Technology Center is the first clinical facility to utilize continuous process sterile isolators, representing a significant advancement in integrating technology into drug development.

Collaboration a key to success
The need to coordinate and manage multiple disciplines was a key element of the BMS expansion project. Flexible, adaptable design, critical construction scheduling and tight budget management were imperative to the project’s success.

To accomplish a project of this magnitude, BMS called upon unique process and facilities engineering and construction talent. For project design development, master planning, construction documentation and administrative services, the company turned to IPS Incorporated, Lafayette Hill, Pennsylvania, a leader in the design of pharmaceutical manufacturing facilities.

In addition to the Facility of the Year Award, BMS was recognized with federal and state government health and safety awards throughout the project. Included among these was the OSHA Voluntary Protection Program Star Demonstration Site award for outstanding safety and health management.

Enhanced speed–to–market is among the many benefits BMS expects to derive from its new facilities. But increased capacity and technical innovation will also help the company meet vital future pharmaceutical development and pipeline needs of medical service providers and patients worldwide.

Sustainable Design and Green Building Tips for Biotech and Pharmaceutical Projects

Sustainable design and green building are becoming major factors in project development. While sustainable design does not necessarily have to cost more, it does involve a bit of planning to ensure it adds value. Whether the request comes from a client, or is simply a practice you would like to implement in your projects, there are a range of steps that can be taken, from very small to very large, to contribute to sustainable design. Below are several tips to serve as a guide during the design/build stages of biotech and pharmaceutical projects to contribute to sustainability.

• Plan Early to Establish Green Goals for your Project.
  The earlier you decide to build green, the more opportunities there are to incorporate cost-efficient sustainable solutions into the design. Having a plan will guide the project team in making decisions and provide an easy way to achieve the company's environmental goals and budget.



• Utilize the LEED® Score Card as a Guide.
  Whether you choose to certify your project or not, utilize the USGBC LEED score card to help establish baseline sustainability goals. The LEED guidelines are a great brainstorming tool and will stimulate the innovation process.



• Utilize Life–Cycle–Costing to Establish “Go/No Go” Hurdle Rates for Sustainable Options.
  For many projects first cost is very important, but being sustainable isn’t about the short-term. It’s about taking a long-term or a life cycle view.



• Site Building for Optimum Energy Performance.
  Utilize the site orientation to take advantage of passive solar energy savings and natural day-lighting.



• Consider an Energy Star Roof.
  Utilize a light color (white) roof to reduce heat gain to the built environment. Dark roofs can be 60% hotter than lighter color roofs and impact the selection of HVAC equipment required to cool the structure.



• Utilize Low-E Glazed Windows.
  Utilize low-E (emissivity) glass. Many manufacturers offer high-performance glazing systems. This higher efficiency glazing reflects more heat and at the same time allows more light to enter the structure. This improves opportunities for natural lighting and ultimately reduces the solar heat gain.



• Optimize Lighting.
  Utilize compact fluorescent and LED lighting to reduce the heat out put and improved efficiency. Take advantage of daylight harvesting. Consider occupancy sensors, and dimming ballasts.



• Utilize High Efficiency Motors and Variable Frequency Drives (VFD’s).
  EPA Studies have shown that VFD’s can save as much as 50% when compared to systems without them.



• Utilize Waterless Urinals and Low-Flow Plumbing Fixtures.
  On average an employee uses approximately 10 gallons of water a day. Green plumbing systems can reduce this to 2.5 gallons a day.



• Specify Recycled Content.
  Many manufacturers utilize recycled materials to reduce overall cost of raw material. There are a wide variety of products available. Incorporate a minimum % of recycled material in product specifications.

Smooth startups start with good commissioning practices

From a strategic perspective, you could say that a pharmaceutical processor’s skill at quickly expanding facilities in response to changing product, market and regulatory needs ranks right alongside research and scientific prowess.

A key factor in bringing new facilities online is commissioning, a function often misunderstood and poorly managed. Commissioning plays an invaluable role in the plant startup process by ensuring that all equipment and systems are designed, installed, tested, and fully operational in accordance with the owner’s design intent.

Commissioning covers all planning, documentation, equipment balancing, calibration and control, performance qualification and other procedures leading up to startup and turnover. Other key elements include operator training and spare parts programs.

A well planned commissioning program will:

• Accelerate project startup


• Produce superior documentation


• Improve online time


• Create a positive commercial impact


• Reduce validation effort


• Ensure a GMP-compliant facility

Though actual practices sometimes vary by project, the Commissioning Master Plan (CMP) is the nexus of an effective commissioning program. It coordinates interaction between contractors, material and equipment suppliers, and internal personnel.

In addition to road-mapping a project, the Commissioning Master Plan assigns team responsibilities and expectations to vendors, monitors performance, and establishes a basis for corrective actions needed to ensure the integrity and success of the project.

In pharmaceutical operations requiring cGMP-compliance, critical utilities and process systems must also undergo validation to satisfy FDA requirements. Occasionally, confusion arises over these terms. But, in a nutshell, all facilities must be commissioned, while only those with cGMP-critical systems undergo validation.

For GMP-compliant plants, Installation Qualification (IQ), Operation Qualification (OQ) and Performance Qualification (PQ) steps are prerequisites for validation, and monitor the following functions:

• IQ ensures installation of the proper equipment


• OQ ensures that equipment and systems operate as required, producing consistent outputs


• PQ ensures that equipment and systems perform to spec and meet process requirements

Risk management-based qualification, espoused by the FDA and incorporated into the ISPE Baseline Commissioning and Qualification Guide, empowers owners to focus primary quality and regulatory efforts on those critical design features and processes that directly impact product and patient safety. This approach ensures that all functions performed by design/contractor teams and vendors meet prescribed quality standards without overlapping or duplicating efforts. By effectively leveraging commissioning practices, owners minimize documentation and redundancy, while reducing qualification/validation time and startup costs.

From a budgetary standpoint, commissioning costs add up to a significant capital outlay, and are frequently underestimated or overlooked. Costs vary greatly according to a project’s scope, complexity and regulatory compliance factors. But it’s important for owners to properly plan and budget for all commissioning-related functions, including: planning, administration, analysis, progress monitoring and reporting.

Another decisive factor in minimizing problems during commissioning and start-up is knowing when and how to work effectively with outside vendors. Pharmaceutical plants comprise a vast network of complex equipment and infrastructure, with few owners experienced in managing renovation and expansion projects of such magnitude. As a result, many are out of their element when faced with such challenges.

To further complicate matters, cost-saving measures, like outsourcing plant engineering, maintenance and operations functions, have drained specialized technical skills from many companies.

As a result, owners could be forced to rely on untested outside contractors to manage critical commissioning and startup operations. In the absence of knowledgeable and experienced oversight, such a massive coordination effort could easily lead to planning and construction errors and delays that eat up capital, delay startup and ultimately slow a product’s speed-to-market.

For best results when establishing design/build partnerships for facility commissioning and startup, it’s important to consider a vendor’s overall project management expertise in conjunction with a high degree of technical know-how.

Finally, by integrating good commissioning practices early in the planning and design process, owners make an investment that pays dividends in time and capital savings, and supports the strategic objectives of the enterprise.

Proper planning prevents poor performance

A growing number of biotech processors are finding wisdom in this axiom taken from an old British Army training manual. They’re recognizing the many benefits of developing third-party engineering partnerships, and integrating them early-on in the master planning process; ideally, at a project’s inception stage.

Pharmaceutical processors operate in a unique environment influenced by many variables, including: capital availability, diverse market demands, complex regulatory standards, global competition, and critical compliance and commissioning requirements. As a result, they must focus assets to best achieve a competitive advantage through innovation coupled with effective cost control and speed-to-market strategies. Accomplishing that requires the highest degree of process/facility design integration driven by comprehensive master planning.

In the traditional process design model, in-house engineers and planners develop a strategic plan and define a project’s parameters. Then, independent engineering and construction specialists are called in to formalize the design and help execute the plan. But there are flaws in that approach which might seriously impact a project’s potential for successful execution.

For starters, internal, organizational dynamics can inhibit objectivity essential to developing plans and processes that support corporate-wide initiatives. To address this, master planners must rise above territorial boundaries and stay focused on key goals. In some corporate cultures, that could present political challenges for internal managers.

In addition, corporate management runs the risk of limiting creative resources at a point where innovation is most critical, during a project’s formative stage. Experience shows that incorrect assumptions made in early planning often lead to costly revisions and construction delays later in a project’s timeline.

Commercial processors who integrate design/build partnerships early in the master planning process report significant, measurable payback for their efforts. In addition to minimizing risks, alliances can help reduce capital outlay and project delays, and cut validation and commissioning costs. These advantages go a long way toward improving a processor’s ability to compete in the fast-paced, changing pharmaceutical marketplace.

For optimum results, a master plan must be aligned with a company’s strategic business goals; and the planning process should involve high level decision-makers within the organization. Management participation is essential to ensure that a master plan supports the new product pipeline, planned acquisitions, cash flow considerations and other strategic issues.

Of course, the real value of planning partnerships ultimately depends on a vendor’s knowledge and understanding of the unique character of the pharmaceutical industry. This means having the expertise and resources for dealing with virtually any facet of the business, from product development and production through quality assurance, packaging and delivery.

When evaluating a design/build partner for master planning, clients should look for comprehensive pharmaceutical experience, preferably on the corporate side. Qualified candidates should demonstrate global vision, along with a track record of providing services to technically complex, compliance-driven industries. Longevity of client relationships is another indicator of a vendor’s stability and capacity to successfully handle challenges, and deliver sound planning solutions to satisfy the needs of all stakeholders within an organization.