9 Oral Solid Dosage Facilities
Edward J. Tannebaum, AIA and Samuel Halaby
CONTENTS
Meeting Industry and Market Needs
Regulatory Pressures on OSD Manufacturing
Environmental Health and Safety
Containment for High-Potency Compounds
Meeting Industry and Market Needs
Advances in Drug Delivery Technologies
Impact of New Drug Delivery Systems
Regulatory Advances of International Harmonization
Business Segment Specialization
Branded, Generic, and Contract Manufacturers
Sales Forecast Effect on Optimization of Processing Equipment
Single-Product versus Multi-product Environment
Production Technology: Yesterday, Today, and Tomorrow
Employee Health and Safety Concerns
Implications for Performance and Compliance
New Greenfield versus an Expanded or Renovated Facility
Delivery and Measurement of Chemical Ingredients, Excipients, Liquids, and Fillers
Milling, Blending, Mixing, Granulating, Compacting, Drying, and Formulation
Compression, Encapsulation, and Specialty Drug Delivery Unit
Coating, Printing, and Inspection
Airlock, Garb Change, and Gowning Requirements
Quality Assurance Requirements
Physical Manufacturing Environment
Special Product Considerations
Provisions for Controlled Substances
Implications for Performance and Compliance
Balance of Engineered Solutions to SOP Solutions
Appropriate Level of Capital Investment
Schedule Advancement Ahead of Scope Definition
Reasonable Level of Quality for the Desired End Product
Reducing the Cost of Products Produced
Outsourcing to Low-Cost Providers
Challenging the Mores and Preconceptions
Comparisons to Other Technologies
INTRODUCTION
This chapter provides an overview of the means and methods of today’s manufacturing technology, the facilities that use these technologies, and the regulatory and environmental employee health and safety challenges that provide the context for ensuring quality. The focus of this chapter relates to the good design practices necessary to develop or upgrade oral solid dosage (OSD) manufacturing facilities.
MEETING INDUSTRY AND MARKET NEEDS
Industry and market needs have increasingly dictated the course of OSD manufacturing. Historically, OSD products date back to the seventeenth century in the United States. Until the 1920s, 80% of the medicines were compounded by pharmacists in liquid, powder, and tablet form. As a result of the health care needs of the military in World War I, high-technology medicines were necessary to treat injured soldiers and cure diseases among war-torn populaces, which became major health issues. The production of tablets of newly created drugs became a prominent industry in the United States. The common OSD products include tablets; hard- and soft-shell gelatin capsules; layered, coated, osmotic, extended-release tablets; and quick-dissolve, extruded, effervescent, powder products.
Current OSD manufacturing is regulated for quality by the U.S. Food and Drug Administration (FDA) and more strictly by international regulatory agencies. Quality and compliance, coupled with selling drugs at affordable prices, provide the background for the development and upgrade of OSD manufacturing facilities with new technology. The variety of products range from highly regulated, branded, and generic drugs to a variety of over-the-counter nutritional products, which have recently been challenged by regulatory concerns and newly enacted compliance mandates.
OSD products (also referred to as small molecules) will continue to be the major source of drug product delivery in the near future. The OSD products are a stable drug delivery form, the least expensive to produce in large quantities, and simpler to produce than sterile injectable products. The future extension of the product life span will revolve around development and approval of newer methods of extended release and formulations that prohibit tampering with the finished dosage form.
Currently, innovations related to tamper-resistant OSD products have proved to be effective in preventing the removal of active ingredients from the finished dosage forms that have contributed to illegal substance abuse in this country.
REGULATORY CHALLENGES
Current Good Manufacturing Practices (cGMPs) related to the elimination of cross-contamination, resulting from airborne exposure, material transfer, and mix-up, are paramount. The increased use of ingredients that are active, potent, cytotoxic, or sensitizing agents has increased the need for upgraded employee health and safety precautions that impact the design of individual processing spaces. This chapter explains the current and imminent changes in the regulatory requirements that are raising the bar of the overall drug manufacturing industry.
MANUFACTURING PROCESSES
DRUG DELIVERY TECHNOLOGIES
Drug delivery technologies are diverse for the various manufacturing operations that range from unitary, manual processes to automated, integrated processes. The technologies revolve around the processes needed to produce both the physical unit dose form and the method of active drug release. Sizes, shapes, and novel forms of delivery provide increased complexity of manufacturing facilities. Alternative methodology for immediate- and sustained-release characteristics for active ingredient absorption creates a range of manufacturing environments for finishing processes, driving OSD development and its subsequent manufacture.
The technologies required for dedicated large-volume operations differ from those used in small-volume, multi-product facilities. The differences in the scale of production are the driving force behind the strategic planning process for successful facility design. The collaboration between the research and development (R&D) scientists of a pharmaceutical organization and the realities of the operations and engineering project delivery requires early intervention to secure the technologies that meet the industry and market needs for quality, compliance, and the best-cost end result. The technology transfer process must consider new systems, processes, and formulations to meet the facility needs of the future.
New OSD technologies that have resulted from the proliferation of novel drug delivery systems and devices provide multiple challenges to the design of OSD facilities. The addition of newly developed technology into the design of a new or renovated facility, before the completion of the product’s development or regulatory approval, creates a need for flexibility in the design, which, in turn, requires an early interface between the facility design team, R&D, and operations staff.
REGULATORY PRESSURES ON OSD MANUFACTURING
International regulatory bodies have established recommendations and requirements for OSD manufacturing, demanding compliance worldwide. Facility-related requirements, based on regulations of the FDA, Saudi Food and Drug Authority (SFDA), Ministry of Health, Labour, and Wealth (MHLW), European Medicines Agency (EMA), Medicines and Healthcare Products Regulatory Agency (MHRA), Therapeutic Goods Administration (TGA), Brazilian Health Surveillance Agency (ANVISA), and other international regulatory agencies, bring a global focus to the critical utility systems, layout, inclusion of airlocks, and single-direction flows throughout facilities. Concerns related to filtration, purified fluid and gas, air installations, cross-contamination, product mix-up, processing visibility, cleaning facilities, and personnel protection for high-potency and sensitizing products, along with gowning facilities, all present differing levels of concern or compliance to different agencies. Multinational product distribution has created the challenge of multiagency compliance at facilities located around the world. Good design practices enable facilities to meet the current design standards that are being harmonized for worldwide conformance.
ENVIRONMENTAL HEALTH AND SAFETY
Environmental health and safety (EHS) play a major role in the design of all facility projects. Involvement of EHS programs ranges from tackling actual risks in manufacturing to the waste stream emanating from liquid and airstreams. Requirements of EHS start from baseline requirements of the Occupational Health and Safety Administration (OSHA) and the Environmental Protection Agency (EPA) in the United States and end with the company standards that are developed. Standards include risk-based requirements for personnel safety from inhalation or skin contact with particulate material that may cause allergic reactions or ingestions that may cause illness. The EHS standards play a significant role in the design of personal safeguards and the segregation, cleaning, storage, and distribution of identified materials produced.
CONTAINMENT FOR HIGH-POTENCY COMPOUNDS
The pharmaceutical industry has established categorization systems to help manage exposure and contamination risks. A typical pharmaceutical company has either a four- or five-band system. For each band, guidance is provided on engineering control measures to be implemented to mitigate exposure risks. Some international regulatory agencies have expressed concern over certain therapeutic drug classes, for example, antibiotics, specifically penicillin; these agencies have therefore demanded a dedicated facility for the production of this antibiotic. Other drug classes, such as cytotoxic compounds, also require dedicated or segregated facilities, depending on the market distribution and regulatory authority. The discovery and registration of drugs that include potent compounds have been on the rise. As a result, many new facilities have implemented enhanced control measures for both a primary (where the product is exposed) and a secondary (where the product has been packaged in a final form but has not received secondary packaging for final shipment) containment. Most process handling for potent compounds is designed for closed operations to provide primary containment through the equipment, and secondary measures are taken in the design of heating, ventilation, and air conditioning (HVAC) systems and airlocks.
CONTINUOUS PROCESSING
Continuous processing is commonplace in most chemical industries; however, it has been slow to be adopted in the pharmaceutical industry. There has been a recent surge in interest as the benefits to scaling out versus scaling up are realized. A few challenges that have held the pharmaceutical industry back from adopting this technology include regulatory aspects of batch definition and process variable changes. The regulatory agencies and pharmaceutical companies are working together to provide new directions on these issues. It is anticipated that in the near future, the industry will register more and more products, implementing continuous processing technologies. This issue is discussed in detail in Chapter 10.
SPECIALTY PROCESSING SYSTEMS
Systems used in specific steps of OSD manufacturing are primarily selected during the development phase of drug R&D. The selection of specific processing technologies is a critical step in the development process. Each new equipment technology or vendor becomes a specific part of the validated drug manufacturing process during the development phase; it is scaled up to commercialized batch sizes during the submission process for a new drug application (NDA) for a branded drug and an abbreviated new drug application (ANDA) for a generic drug.
The vendor-specific technical requirements become a critical part of the design for OSD facilities, in terms of the size, weight, access, and mechanical, electrical, and critical utility loads. Connections to the coordination of the engineered processing systems are the major focus of the planning of the OSD facilities. These spaces must not only meet initial processing requirements but also may be the baseline for creating more flexible space that may be required if equipment changes or modifications are required for future OSD products.
SUSTAINABILITY
Sustainability in the design of pharmaceutical facilities is reviewed on a project-by-project basis. Today’s design goals for energy conservation have a direct impact on the cost of products due to the high cost of utilities to drive the critical engineered systems in these facilities. The inclusion or exclusion of these sustainable features is driven by the client’s corporate philosophy and also by the restrictions of the return on investment (ROI) in terms of months or years achievable. Sustainability is discussed in detail in Chapter 16.
SMART BUILDINGS
“Smart buildings” have become a critical aspect of some large pharmaceutical OSD manufacturing facilities, primarily for large-scale, dedicated product plants. The initial capital costs, which are large, and the subsequent challenges to validating these facilities have minimized their presence in the industry. The ongoing challenges of maintaining the buildings in a validated state, combined with the rapidly advancing changes in building management technology, have created an environment that may make it difficult to maintain these buildings both financially and operationally.
MEETING INDUSTRY AND MARKET NEEDS
The business climate in the pharmaceutical industry has changed as a result of mergers and acquisitions of large and small manufacturers and also the international nature of the pharmaceutical business. The international approval and distribution of products requires that manufacturers adjust their supply chain philosophies to meet a variety of needs. Different regulatory agencies require different manufacturing mandates as to where drugs are manufactured, as well as regulations of products that are imported. Transfer of product formulations between countries can be limiting factors in the exportation of drug manufacturing technologies. This international business transition has also created a lower cost of goods, as certain locations and labor for manufacturing are more profitable, which is reflected in the bottom line of the business. The shift in the locations of manufacturing has created a need to design facilities that are technically equivalent, yet meet local construction material and system availability for installation, maintainability, and overall quality standards. These new challenges require vigilance during the design effort to ensure the long-term capability of these installations.
ADVANCES IN DRUG DELIVERY TECHNOLOGIES
Drug delivery technologies have changed over the past 30–40 years. While the basic technologies have not changed, the equipment advances have increased throughput and improved overall manufacturing speed, consistency, and quality.
To minimize cross-contamination, equipment has been developed to contain particulate material. Advances in equipment design to meet handling requirements have resulted in fully contained equipment with sealed product transfer, both loading and unloading of equipment, and wash-in-place (WIP) systems that provide product cleaning without the need for human intervention. With the increasing need for equipment to handle the highly potent, sensitizing, and cytotoxic products, these contained, self-cleaning additions to equipment have increased the need for space and segregation to accommodate the equipment sizes, needed clearances, and significant increases in capital spending requirements.
Primary equipment selections no longer focus on exposed product processing equipment, such as open dispensing, sieves, milling, open blenders, hand-scooped transfers, and drying ovens. Any point of open product to the airstream should be avoided to eliminate cross-contamination of materials and products.
IMPACT OF NEW DRUG DELIVERY SYSTEMS
Some of the new forms of drug delivery include products that dissolve transmucosally for a convenient and faster method of reaching the bloodstream. Other new forms include dissolvable strips with active medication, micronized powder inhalation devices, and extruded formulations that limit the adulteration or tampering with the final dosage form. These tamper-resistant drug delivery forms are used with highly addictive products, such as fentanyl (Actiq and Durogesic), and are becoming the preferred method of dosing-controlled substances.
The ability to re-create and reformulate existing drug molecules, especially those reaching their patent expiration, enables drug producers to file with the FDA for a NDA, thus extending the life of their proprietary product or converting a generic product into an ANDA for higher profitability.
REGULATORY ADVANCES OF INTERNATIONAL HARMONIZATION
Harmonization of international regulatory agencies has been a movement that has spread over the past 10 years, affecting both aseptic manufacturing and OSD manufacturing, which has achieved greater harmonization in international arenas than in the United States. International regulatory bodies have expectations for the harmonization of many products, including segregation of high-risk product processing, while the FDA has mainly addressed only penicillin and cephalosporin products.
Due to the international distribution requirements for most drug products, high-level international standards are the preferred method of achieving current and potential future compliance, anywhere in the world. Concurrence with the most stringent international area served would be the most prudent direction to take, whether it is the European Union (EU) for Europe or ANVISA for South America. These organizations generally are the most prominent and specific in defining design requirements.
BUSINESS SEGMENT SPECIALIZATION
Branded, Generic, and Contract Manufacturers
Distinctions among branded, generic, and contract OSD manufacturers historically were common in their manufacturing facility design. The cost of goods was a driving force among these business segments, primarily as a result of the total ROI each segment was able to generate. As the level of regulatory compliance has risen worldwide, the disparity in the facility attributes has narrowed significantly. Branded drug producers have streamlined their operations and facilities to lower the unit cost of the goods produced.
Branded Drugs
These drugs are still under a patent. These drugs have received NDA approval from a governing regulatory body and been approved after a three-phase clinical trial process by that regulatory body.
Generic Drugs
These drugs are similar to NDA drugs and have been approved through an ANDA application after the expiration of the drugs’ patent. These drug “similars” are approved without clinical studies and contain within 10% the equivalent active content of the NDA version of the drug. Generic manufacturers are constantly raising their level of compliance and parity with branded manufacturers. Their need to improve their image, relative to agency compliance and rapid response to aggressive ANDA product introductions, together with ANDA approval exclusivity, is mandated to garner market share for a limited window of commercial opportunity.
Contract Manufacturers
Contract manufacturers pose the greatest challenge. Facilities must remain in full regulatory compliance, while at the same time reaching levels of compliance to meet various customer audit mandates. Combining the regulatory and customer requirements with an industry that is driven by a competitive cost of goods requires manufacturing facilities to be the most cost-effective in the pharmaceutical industry. The expanding world of pharmaceutical outsourcing to contract manufacturers is creating a new class of facilities that must meet the regulatory requirements to satisfy customers and service providers alike (Table 9.1).
Sales Forecast Effect on Optimization of Processing Equipment
Sales forecasts are the baseline capacity requirement for most OSD facilities. Sales forecasts are based on data that are driven on anticipation of usage by government agencies, hospitals, physicians, and consumers, along with the realities of competition. Government agencies are by far the largest purchasers of drug products in the United States, in particular. The forecasts are initially based on timelines relating to regulatory approvals and projected launch dates. Many factors impact the accuracy of the sales forecasts; thus, great care must be exhibited in using these data at face value.
Operations and engineering professionals, who must quantify the relationship between the dosage unit requirements and the sizing of the manufacturing facilities, must understand the assumptions of the forecast baseline requirements. This understanding is vital in producing a consensus as to the quantification of the manufacturing equipment need and the overall optimization of the facility design. The company philosophy related to batch sizes, equipment sizing, capacity utilization, changeover, and WIP abilities plays a role in the development of a strategic plan for purchasing manufacturing equipment.
Optimization of manufacturing equipment, upon acceptance of a sales forecast by management, is a balance between operations, quality assurance, quality control release, and actual order receipt or inventory requirements. The sizing and optimization of equipment are calculated based on a downstream evaluation of increased run capacity to minimize bottlenecks and maximize the output of the entire process.
TABLE 9.1
Comparison of Branded, Generic, and Contract Manufacturers
FIGURE 9.1 Static simulation graph for a typical tablet product.
A typical optimization model is illustrated by the static simulation graph for a typical tablet product (Figure 9.1).
Similar models are performed for individual processing steps, including multiple products, with simultaneous manufacturing operations. This is discussed in more detail in Chapter 10.
Management Preferences
Branded manufacturers develop products for both large-scale production and small, niche markets. Each of these widely divergent markets requires significantly different types of facilities to optimize manufacturing and maintain the lowest cost of goods produced. Large, branded manufacturers with large-volume products traditionally have made large capital investments in their facilities. Large investments are usually directed at creating automated, high-throughput facilities, increased yield rates, and a reduced labor cost per unit produced, thus minimizing the risks in achieving the major financial objectives for the drug.
Small-volume, niche market–focused branded drugs are traditionally manufactured in older, less automated facilities, with unit operations. The concerns for volume throughput and major financial objectives relegate this segment of their brands to their “dog and cat” operations (this refers to products that have a small demand and sales volume). The small-volume products are important segments of a company’s market penetration strategy, especially if they are for unmet medical needs (i.e., an orphan drug).
Generic manufacturers focus on a product mix that is usually driven by a specific segment of drugs, for example, oncology, hormone replacement, cardiology, beta-blockers, gastroenterology, and dermatology. Their choice of drug type relates to the complexity of its manufacturing level to reduce potential competition or simplified compounds, requiring shorter ANDA approval schedules, or the specific branded competition resistance to potential patent challenge litigation.
The manufacturers of ANDA drugs traditionally use unitary processes because of the financial viability and life cycle of their products. Multiple product plants are commonplace and require a level of investment that keeps their profit margins at the very highest level possible. Modest capital investments in facilities and overall facility overheads are commonplace in this arena. Manufacturing equipment for generic manufacturers and the overall level of regulatory compliance have risen over the past decade to a level equivalent to that of branded manufacturers.
Contract manufacturers are a growing resource to both branded and generic manufacturers. Whether it is an outsource manufacturer for a single product, an overflow resource, or the expert in specific processing and drug delivery technologies, the primary focus is on speed to market and cost of goods. Quality assurance is considered a baseline expertise that is built into the manufacturing operations of the contract manufacturer.
Unitary capabilities (i.e., individualized processing capabilities) with a high degree of cross-contamination controls are a requirement that is paramount. The manufacture of multiple products in adjacent spaces creates the need for facilities with validatable HVAC and critical utility systems that ensure compliance with each of their customer’s quality concerns. Quality and regulatory compliance are givens and are mandated in each of these distinctly different manufacturing segments.
Single-Product versus Multiproduct Environment
Single-product facility design provides a platform for the innovations that enable a branded producer to maximize throughput, without the restrictions created in a multi-product plant. Manufacturing equipment selections are driven on product transfer capabilities that maximize equipment use and reduce downtime. Special material handling issues, related to potent and cytotoxic compounds, are more readily achieved in single-product plants due to the clear definition of a single process. Manpower and personnel protection issues can be dealt with one well-thought-out method, thus minimizing risk.
The multi-product plant environment is one that must deal with competing needs on a regular basis. Cross-contamination, product mix-up, and cleaning issues are just some of the issues that must be addressed through engineering and procedural solutions. The life of a multi-product facility design is ever changing and requires an adaptable layout; a set of critical utility and HVAC systems; and purified water, gases, steam, and hot water that can meet changing capacities and distribution needs. Quality assurance concerns for this changing work environment are vital components of a design solution that maintains regulatory compliance.
PRODUCTION TECHNOLOGY: YESTERDAY, TODAY, AND TOMORROW
Drug manufacturing processes have made a gradual transition over the past century. While tablets or soft gelatin capsules have been the principal dosage forms used for many years, new OSD forms have evolved, including quick-dissolve tablets or wafers, sustained-release capsules, and film technologies for rapid drug solubility. The manufacturing technology that produces these drug forms is primarily divided into the following categories: (1) sampling, dispensing, or handling of active solid or liquid chemicals and excipients; (2) alteration of particle size, granulating, mixing, drying, and milling; (3) compression and encapsulation; (4) coating and printing; and (5) primary and secondary packaging.
MANUFACTURING FLOWS
Currently, OSD facilities are designed with distinctive flows to minimize cross-contamination and meet the intent of cGMPs for separation of products and activities. Flows related to personnel movement, gowning facilities, materials management, waste removal, and cleaning have become major components of pharmaceutical facility design. The flows that are mandated for sterile manufacturing should not be equated to the design of OSD facilities. The design of flows for OSD facilities should be weighed against specific project concerns related to cross-contamination and product mix-up, while maintaining the physical environment for each specific project. The relative throughput of the facility must be a governing factor in the design of all OSD facilities. The actual traffic of materials, personnel, and waste should dictate the degree of concern for the crossing of flows and the risk that is present during day-to-day operations (Figure 9.2).
FIGURE 9.2 Typical OSD manufacturing block flow diagram (BFD); other BFDs are discussed in Chapters 4 and 10.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
