John S. Holton
CONTENTS
General Packaging Plant Design
Raw Material and Finished Goods Warehousing
Packaging Space, Equipment and Process Relationships
Secondary and Tertiary Packaging Areas
Testing Labs and Other Quality Control Areas
Refrigerated or Frozen Storage
Future Developments: Packaging Trends
Special Discussion: Radiofrequency Identification
Speed and Operational Effectiveness
INTRODUCTION
This chapter covers good design practices for packaging and warehousing facilities. It discusses the principles that are applied to packaging and warehousing facilities and addresses the critical function of a packaging facility to prevent product mix-ups and cross-contamination. It covers the steps needed to construct a new facility or renovate an existing one, and it describes the function and purpose of packaging and warehousing pharmaceutical product, the multiple levels of packaging areas, critical parameters, and utility system criteria. Chapter 11 specifically addresses sterile packaging, which will not be discussed here. The same hygienic zoning principles (i.e., white, gray, black, transition, and proper gowning techniques) that apply to pharmaceutical processing also apply to pharmaceutical packaging (see Chapter 15 for a description of hygienic zoning principles).
To assist the design engineer and associated team members for a given project, this chapter reviews the initial stages of a project through to the commissioning and qualification and turnover stage. It discusses the items that should be reviewed and documented before initiating a project. The application of risk management is presented to determine the critical components of the project to ensure product and personnel safety and project cost control. The fundamental design principles, the packaging process, and associated space interactions are provided. Facility layout and construction materials are discussed. Design considerations for utility systems (e.g., heating, ventilation, and air conditioning [HVAC] and electrical) are identified, as well as support systems (e.g., compressed air and vacuum). Typical design criteria are described, as well as the mechanism by which to document attainment of certain parameters, such as temperature control.
PACKAGING DEFINED
In its simplest terms, packaging is preparing goods for transport, distribution, storage, retail, and use. Packaging has evolved from simple clay pots and woven bags into the multi-billion-dollar industry that it is today. Primitive packaging was not concerned with the containment, protection, transport, and information or sales functions of modern packaging. Today, demographic studies provide firms with data that help them make smart decisions about packaging design, graphics, and marketing. While navigating regulatory and environmental hurdles, firms are now concerned with the four R’s:
Reduce: The amount of packaging material in any given application is minimized without jeopardizing the integrity of the goods within.
Reuse: Whenever possible, packaging systems that can be used over and over again are created.
Recycle: Used packaging materials are collected to be reprocessed into new material.
Recover: Rather than send packaging material to a landfill, it is collected and reused.
IMPORTANCE OF PACKAGING
In the course of packaging operations, preserving the integrity of the drug product and the safety of the patient is of utmost importance. The Food and Drug Administration (FDA) ensures that drug products are suitable for their intended use by making certain that companies that manufacture drug products follow very specific guidelines during the manufacturing process. The same federal regulations that govern the manufacture of drugs apply to the packaging of these products for distribution and sale. From the time the drug product is approved for packaging and distribution until it is prescribed, purchased, and used by the consumer, it is the packaging systems that provide the means to ensure that the safety, efficacy, strength, and purity of the drug product are not compromised. For the purposes of this chapter, only packaging for finished pharmaceutical products, medical devices, and other industry-specific applications (e.g., current Good Manufacturing Practices [cGMPs]) is discussed. The term drug product is used to collectively describe the applications in this chapter.
PACKAGING FUNCTIONS
There are four rudimentary packaging functions that must be evaluated during the packaging design process. They are discussed below.
Contain Function
This function is concerned with providing a receptacle to keep some quantity of product together in a single mass. When programming for the contain function, the package designer must consider the physical attributes of the product (e.g., solid, liquid, granular, paste, or discrete item), the product’s nature (e.g., corrosive, volatile, flammable, toxic, or pressurized), and the quantity of material to be packaged.
Protect and Preserve Function
All package contents must be protected from cross-contamination and physical damage, such as vibration, abrasion, extreme temperatures, and humidity. Child-resistant, package-opening features are required by law on some drug products. Tamper-proof features have been prevalent since the first Tylenol tampering incident in 1982, and antitheft and anticounterfeit measures may be used as well. The preserve function pertains to stopping or inhibiting chemical degradation of the package contents; for example, oxygen, water vapor, and light are potentially damaging to certain drug compounds, and barriers to these elements are critical to preserving the integrity of the drug product.
Transport Function
The transport function is applicable to unit loads (skid quantities) of goods; however, proper package design for transportation starts at the primary packaging stage. Transportation is always seen as hazardous in some way to the product being moved, so this is an important design feature.
Inform and Sell Function
In clean industry applications, the inform function gives the consumer specific information about the contents of the package. There are regulatory requirements that dictate what information appears on the primary package. Some of this information is preprinted (e.g., drug name, strength, quantity of doses, and drug manufacturer), and some is printed in real time on the packaging line (e.g., lot or batch number and product expiration date). There is printed information at all levels of packaging, even on the drug product itself in the case of tablets and capsules. The drug name, the strength of the dose, the total quantity of doses, and the name and address of the drug manufacturer are absolute minimum requirements for preprinted information. Most printed information appears on the unit of sale, usually the secondary paperboard carton. In the case of prescription medications, there is also preprinted information for the physician or patient in the form of a folded package insert that is placed in the carton with the bottle, pouch, or blister.
Typically, prescription medications have minimalistic packaging because physicians prescribe these medications, so the consumer does not have an opportunity to compare one product to a competitive product. The over-the-counter (OTC) packages, however, compete directly with other medications on the store shelf, and drug manufacturers go to great lengths to differentiate their products from those of their competitors.
LEVELS OF PACKAGING
Primary Packaging
The primary package, the first level of containment, is in direct contact with the finished drug product as a blister card or pouch for tablets or capsules; a glass or plastic bottle for tablets, capsules, powders, or liquids; a glass or plastic syringe, ampule, or vial for injectable drug products; or an aluminum or laminate tube for creams and ointments. This first level is critical to maintain the safety, efficacy, potency, and purity of the drug product. Primary packaging is the level most important to the shelf life of a drug. Some drugs are susceptible to water vapor or carbon dioxide and others to oxygen or light. Certain packaging materials resist these threats, although there is no universal barrier. Some packaging materials use a laminate structure, combining the benefits of two or more materials in a single, multilayer barrier.
The dosage form is directly exposed to the packaging room environment after it is removed from its bulk container and before its introduction to the primary package. This necessitates the use of strict engineering and environmental controls during the primary packaging process to ensure that the drug product is not compromised.
Secondary Packaging
Secondary packaging consists of one or more primary package units contained within a secondary container, usually a paperboard carton or tray. Any supplementary components, such as patient and physician instructions or sales and marketing materials, are added at this level. This level of packaging is the unit of use for prescription products, and for OTC products, it is the package first seen by the consumer on the store shelf; therefore, it is graphics intensive.
Tertiary Packaging
Tertiary packaging is most commonly employed with OTC formulations, usually reserved for bundling together multiple units of use into units of sale at the wholesale level. Examples are stretch banding, shrink bundling, and overwrapping. Tertiary packaging makes it easier to configure distribution loads for shipment and break down distribution loads at the point of sale.
Distributive Packaging
Drug product packaged for sale is usually placed in corrugated shipping containers for distribution. These containers have a prevalent shipping label to comply with regulatory requirements associated with lot number and expiration dating. Corrugated shippers can be palletized into a unit load, or they can be distributed in quantities as small as a single case.
Unit Load
Entire lots of packaged drug product bound for warehouses or distribution centers are usually unitized in pallet quantities. Corrugated cases are stacked, interlocked, and stored in warehouses to await shipment to the consumer.
WAREHOUSING
Warehousing operations should provide appropriate control to prevent contamination or mix-up of materials, containers, closures, packaging, and labels. Storage of finished product or intermediate or raw product materials may need special environmental conditions. Drug products should be stored under appropriate conditions of temperature, humidity, and light so that the safety, identity, strength, quality, and purity of the drug products are not affected.
Specialized, independent storage and handling areas may be needed based on the material considerations identified in the risk analysis, due to environmental health or safety hazards or regulated status as a controlled substance. Controlled access should be employed, as necessary, in the facility.
GENERAL PACKAGING PLANT DESIGN
A pharmaceutical packaging plant can be a stand-alone, dedicated facility or part of a larger manufacturing and warehousing operation. A pharmaceutical company often builds a packaging plant and a warehouse, with future plans to allow packaging to expand into the warehouse area and build additional warehouse space as necessary. Careful consideration must be given to this approach, so that maximum use of vertical warehouse space can be realized when it is converted to packaging space. Adding mezzanine areas for office space and mechanical equipment, such as HVAC systems, is a way to maximize the old warehouse space overhead. Additional general considerations include:
Areas containing products with potentially hazardous properties that might be released during warehousing (i.e., during sampling, weighing, or dispensing) or primary packaging operations need special consideration. Finishes and environmental conditions for these areas should be equivalent to those used for open processing of exposed products.
The design should provide adequate lot and material segregation to prevent contamination or mix-ups. Segregation can be implemented by spatial (physical), temporal (time), electronic, or procedural means. The evaluation of segregation requirements is modified based on a review of the risk assessment factors.
The design should comply with applicable fire and safety codes, accessibility guidelines, and environmental regulations.
Material staging should address the environmental state for the product and raw materials; for example, a product might need staging at 36°F–46°F (2°C–8°C), while labeling materials associated with packaging may need humidity or light controls. Access control and security monitoring of areas may be required.
PRODUCT EXPOSURE
Product exposure is generally classified as nonexposed or exposed.
Nonexposed Products
When product or material is not exposed to the environment, the risk of contamination is minimal (e.g., transfer of finished product by pneumatic transfer, vacuum transfer, or bin transport). Facility requirements, such as architectural, HVAC, and environmental controls, may be reduced.
Exposed Products
When product or material is exposed to the environment, there is potential for contamination of or from the environment. This often requires airlocks and directional airflow, increased ventilation and filtering of air, or heavy reliance on standard operating procedures (SOPs) to reduce potential cross-contamination, such as an operator tracking product or material from one area to another. Increased potency or toxicity of product or material often requires increased levels of protection for the packaging process, primarily to protect personnel and the environment.
USER REQUIREMENTS
Decisions and commitments made in the early phase of project planning are often too costly to change as the project advances to final design and then to execution. Therefore, developing user requirements for the facility before initiating the design process is critical in setting the schedule for the overall delivery for the facility.
To be effective, user requirements should be concise and germane. While it is possible to produce one document that covers the entire scope of a facility, a hierarchy of documents is more effective. User requirements should be well understood and properly applied. Data relevant to developing user requirements should be gathered on the following:
Process. Critical environmental parameters that should be achieved, maintained, and monitored
Quality. Regulatory guidance and quality principles to guide decision making on facility parameters that can affect product quality and patient safety
Operations. Appropriate environment for the working conditions that affect facility design
Maintenance. Critical aspects of the facility design that ensure a low total cost of ownership (TCO) of the specified life of the facility
Within the user requirements, quality requirements should be separated from business or other requirements. The number and titles of these documents will depend on the project size and scope. Documents listing user requirements may include the following:
Project charter. A high-level description of the requirements, including descriptions of the facility capability, the potential for expansion, and corporate architectural requirements.
Facility user requirements specifications (URSs). A concise document that provides the design brief from the organization to the designer, listing any company standards or specifications to be used.
System URSs. A concise document that provides the design brief from an organization to the designer, listing any organization standards or specifications to be used; typically, these are provided for quality-critical systems. The scope of work usually needs designers to develop the design specifications for supporting systems.
User requirements can be stated as performance-based information that describes an operation and sets expectations where critical process parameters (CPPs) are well defined (e.g., temperature or relative humidity) as acceptance criteria (required results) or as expected results where some variation may be acceptable. For performance-based information, the facility designer should gather relevant information and propose expectations that would meet user requirements. Where the rationale for criteria at one facility is well understood, those criteria may be reproduced at a similar facility. Variables involved should be understood, and the facility designer should carefully consider each of these variables when proposing criteria. A formal URS document should provide a vehicle for exchanging information between business units and the design team. The URS should help to:
Ensure team consensus on project scope, facility use, and functional requirements
Achieve business objectives for which design options can be assessed and determined
Generate an understanding of product and process specifications
Focus design review and design verification and subsequent commissioning efforts
The URSs are a starting point of a process to facilitate compliance with cGMPs and other regulations. Primary regulatory requirements include that “any building or buildings used in the manufacture, processing, packaging, or holding of a drug product shall be of suitable size, construction, and location to facilitate cleaning maintenance and proper operations” (21 CFR 211.42[a]) [1].
Parameter-focused designs decrease the risk of cross-contamination and product and label mix-ups. This chapter defines key parameters to identify and analyze risks to patients, product, and employees, as well as to promote compliance with applicable regulatory requirements. “The design of any such building shall have adequate space for orderly placement of equipment and materials to prevent mix-ups between different components, drug product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination” (21 CFR 211.42[b]) [1].
The facility user requirements can be outlined and incorporated into the design.
Knowing and having a scientific foundation on which products and processes are developed is considered critical to defining the quality aspects and controls needed to design, build, and maintain a compliant packaging and warehousing facility. Once complete, the requirements and product quality aspects that have been identified per product or system should be implemented at each facility producing or processing the same products.
RISK MANAGEMENT
Controlling material mix-ups, contamination, and material storage conditions is a major consideration in designing packaging and warehousing facilities.
Risk management is a systematic application of management policies, procedures, and practices to the task of identifying, assessing, controlling, and monitoring risks. It is typically an iterative process. It should be based on robust science and product and process understanding (i.e., an understanding of critical quality attributes, which are based on and traceable back to the relevant regulatory submission). Qualitative or quantitative techniques may be used. The focus should be on the risk posed to patient safety and product quality. Risk management should reduce risks to an acceptable level. Complete elimination of risk is neither practical nor necessary.
A framework for making risk management decisions should be defined to ensure consistency of application across functions and departments. Such a framework can be effectively implemented when it is incorporated into a comprehensive quality risk management system.
No one tool or set of tools is applicable to every situation in which a quality risk management process is described. International Conference on Harmonisation (ICH) Q9 provides a general overview of and references for some of the primary tools used in quality risk management by industry and regulators and should be referenced in the application of the facility risk assessment [2]. The International Society of Pharmaceutical Engineering (ISPE) Good Practice Guide Applied Risk Management for Commissioning and Qualification provides more information on the use of risk assessment for commissioning and verification [3].
A full risk assessment should evaluate all of the systems and their interrelationships, including the facility, utilities, equipment, cleaning, storage, materials, procedures, controls, qualification, validation, maintenance, and records. When starting the risk assessment process, it is critical to define the system boundaries. Once defined, the scope of the project can be defined. The team size should be maintained at about six to eight people and should comprise subject matter experts from manufacturing, operations, engineering, processing, maintenance, quality, customers, and suppliers. In keeping with the focus of patient safety, product quality, and data integrity, the following list includes some of the common hazards for a packaging and warehousing operation: (1) distribution of adulterated product; (2) product mix-ups; (3) label and labeling mix-ups; (4) contamination; (5) misbranded product; (6) legibility and content of the label (e.g., lot number, expiration date, and all bar codes); (7) records integrity; (8) label reconciliation; (9) yield reconciliation; (10) package integrity (package performance); (11) product protection from exposure to detrimental temperature, humidity, or light; and (12) quality system oversight.
PACKAGING FLOOR LAYOUT
The packaging plant is laid out with packaging rooms in a grid pattern; the integrated design should satisfy the project specifications and address risk assessment factors, while providing good levels of access for operability, maintenance, cleaning, personnel, product, component raw material, waste, and trash movements. The intent should be to keep all packaging areas as centralized and equidistant from support areas as possible. The material staging specification must address the line clearance philosophy. This staging does not need to be in a separate room, but in a separate area (spatial segregation), which may facilitate production and reduce risks in multiproduct facilities or facilities with high throughput. If there are adjacent packaging lines, there should be adequate control to ensure prevention of mixing up materials, leaflets, or labels. Typically, this control is a barrier that extends to the floor; for example, if a leaflet is dropped, there is no risk of it being transferred to an adjacent packaging line.
Building columns are designed into walls so that the packaging rooms are free and clear for maximum flexibility with respect to equipment layout. Glass can be used to give the plant an open feeling and allow supervisors and inspectors to view the work in process; however, the cost and safety implications must be factored into the final design. Hallways should be large enough to permit the flow of materials and personnel and also to facilitate the movement of packaging equipment. The lengths and widths of the largest machinery used must be determined, and the means by which to move this equipment from the receiving dock to any packaging room and back out to the maintenance and storage areas must be designed into the packaging plant layout.
RAW MATERIAL AND FINISHED GOODS WAREHOUSING
Maximum throughput is realized when there are dedicated warehouses for raw material and finished goods, and the flow of material is linear. It may appear that these warehouses function in a similar fashion, but they actually operate quite differently. A raw material warehouse is typically high bay, with large volumes of palletized packaging components stored in racks until requested by the packaging floor. Material pulled from the warehouse can be sent to a variety of packaging rooms. There is a great diversity of materials stored in the warehouse—everything from heavy, dense rolls of blister films that can weigh more than 1,000 lb per pallet to very light pallets of flattened, folded, corrugated, shipping cases. Components, such as bottles and caps, take up a lot of warehouse space, and most firms use a just-in-time ordering philosophy with their suppliers to minimize the quantities of these materials that must be stored on-site.
A finished goods warehouse consists of pallet loads of finished product in shipping cases that are ready for distribution. These loads are typically uniform and are floor stacked as many as four pallets high. Trucks are loaded with pallets two units high, so it is efficient to store finished goods two to four units high to minimize fork truck motions. Finished goods usually remain in the warehouse only as long as it takes for the quality assurance department to review the packaging batch record and approve the batch for shipment.
Warehousing operations must provide appropriate control to prevent contamination or a mix-up of materials, containers, closures, packaging, and labels. Storage of finished product or raw product materials may need special environmental conditions and temperature mapping to ensure that conditions in the warehouse meet requirements. Significant changes in humidity may affect the physical properties of cartons, causing variation in line performance (see the “Package Design Principles” section for information relative to temperature mapping requirements). Materials should be stored in a manner that allows for cleaning and inspection.
PACKAGING DESIGN PRINCIPLES
Packaging facilities should be designed to allow product, packaging components, work in process, finished goods, and waste to move through the plant in sequential order. Material flows are designed to prevent cross-contamination. Packaging areas must allow adequate space for materials, equipment, and personnel. In addition, space must be provided for operation, maintenance, and cleaning of packaging equipment. Separate areas are designated for packaging operations, equipment cleaning, storage of clean equipment and tooling, and storage of dirty equipment and tooling. Exposed product processing that requires a controlled environment may need personnel gowning, airlocks, high-quality room finishes, and a cleaning regimen to protect the product. Restrooms and other personnel convenience areas should not open directly into primary or secondary packaging areas. Exposed wood pallets and other wood products should not be used in primary packaging areas where direct product exposure is possible. All HVAC systems should be designed to prevent cross-contamination and infiltration of extraneous matter. Proper filtration must be provided in areas where contamination is a possibility. Architecturally, horizontal surfaces should be avoided (e.g., use sloped sills) to minimize the collection of particulate matter.
PACKAGING PROCESS ASSESSMENT
Before undertaking a detailed facility design, a thorough study is necessary of the current and potential future packaging process parameters. The results of this assessment should be contained within the facility and system user requirements. The following outline can be used in this assessment:
Product. Toxicity, sensitivity, drug classification, number of stock keeping units (SKUs), stability requirements, dosage form, package format, packaging materials, and labeling
Production. Campaign, changeovers, product mix, scale, clinical versus commercial, batch size, number of lots, throughput speeds, and number of lines
Quality assurance. SOPs, validation, reject rates, quality inspections, exception handling, pest control, and cleaning procedures
Equipment. Dedicated and multiuse, primary, secondary, tertiary, fixed and portable, changeovers, automation, accumulation, backup, redundancy, tooling, and spare parts
Personnel. Accessibility, flow, training, biometrics or passwords, gowning, and workstations
Logistics. Fork trucks, battery charging, storage racks, cold storage, quarantine, hazardous materials, and controlled substances
Environment and safety. Occupational Safety and Health Administration (OSHA); Environmental Protection Agency (EPA); personal protective equipment; SOPs; confined space; environmental monitoring; lighting levels; sound levels; and fire safety, including possible containment of water used to extinguish a fire
Support facilities. Restrooms, locker rooms, break rooms, cafeteria, nurses’ station, label storage, and retained sample storage
Utilities. Compressed air, electricity, vacuum, and specialty gases
PACKAGING SPACE LAYOUT
In designing packaging space for pharmaceutical and medical device applications, care must be taken to protect the integrity of the product. The cGMP regulations state that operations should be performed within specifically designed areas of adequate size (21 CFR 211.42[c]) and that procedures should be in place for prevention of mix-ups and cross-contamination by physical or spatial separation from operations on other drug products (21 CFR 211.130[a]). Care must be taken in providing facility design to mitigate or completely eliminate these risks.
Packaging areas are typically located adjacent to manufacturing areas, the raw material warehouse, and the finished goods warehouse. Ideally, drug product and packaging components flow into one end and finished goods out of the other end of the process. The waste streams created by the packaging process must also be considered. Before a detailed design is created, a flow diagram of the packaging process is constructed to show all process inputs and outputs and all points of operator intervention. During the design stage, the design and engineering firm must have access to accurate electronic drawings of the packaging processes, including plan views, equipment elevations, and utility connection points. Packaging suites are relatively clean areas with high levels of activity, noise, and movement. This is the opposite of processing areas where most of the work takes place out of sight from operating personnel in closed systems. Thus, most firms want packaging areas to include large viewing windows where packaging processes can be viewed from an area where gowning is not required.
Spatial Requirements
Packaging areas require adequate floor space for equipment, personnel, and materials. Entrances to packaging areas must be properly sized so that the largest piece of equipment needed for a given process can be moved into and out of the space without building modifications or service interruptions. A minimum of 5 ft should be provided between equipment and packaging area partitions to provide access to power panels, allow for the movement of equipment and materials, and provide safe egress for personnel in the event of an emergency. In a well-designed packaging process, all operator interventions should take place from one side of the line. This includes regular adjustments; charging the line with raw materials, such as bottles, caps, labels, foil and film, folding cartons, and package inserts; and removing finished goods from the line. Dimensionally, packaging spaces should be designed to maximize equipment use while minimizing space.
Safe Egress
Because of the linear nature of automated packaging processes, the complete line layout, including skids of packaging components, must be factored into safety plans. Some automated lines can be as long as 150 ft or more, and equipment could possibly compromise paths to emergency exits. Additional exits may be needed, or line crossovers can be used as necessary.
Ceiling Height
In most applications, in both primary and secondary packaging suites, ceiling height should not be less than 10 ft. In instances where drug product is fed from above, a ceiling height of 14 or even 16 ft may be applicable. In every case, the equipment manufacturer or packaging line integrator must be consulted to determine the maximum height needed for the equipment.
Lighting
Lighting fixtures should be accessible to allow proper maintenance, such as changing bulbs and repair or replacement of the ballast. Lighting fixtures used in exposed protection areas should allow for cleaning and be able to withstand the pressure and temperature of any water streams used for washdown. Lighting levels between 60 and 75 foot-candles are generally sufficient for most packaging operations. Some areas may need higher foot-candles if there is an online inspection task, for example, to be performed, or perhaps lower foot-candles if there is a backlit automatic machine-based inspection. Most of the automated inspection areas tend to be shrouded, and adjustment of local lighting levels is not required.
Packaging Space, Equipment and Process Relationships
Primary packaging operations are followed in-line by any number of secondary and tertiary processes (i.e., it is a linear process). Individual machines are linked to each other by a series of conveyors, and logical process controls and buffer zones provide an integrated packaging operation. Some processes are highly automated, with minimal operator intervention, while others are entirely manual, with operators performing all machine functions. The factors that dictate the degree of automation include equipment costs, operating costs, labor rates, desired throughput, and the duration of the packaging campaign.
Packaging lines are usually arranged either in a U-shape, with the beginning of the line and the end of the line located in the same general vicinity, or straight through, with the beginning and end of the packaging process located at opposite ends of the packaging area. The design method is impacted by the general plant layout, but there are distinct advantages and disadvantages to each method. In a U-shaped design, the packaging area tends to be operator-centric, with the man–machine interface located on the inside of the U. The operation can be centrally supervised, and one operator can manage multiple machine stations. All staged packaging components, such as foil, cartons, and package inserts, are also located on the inside of the U. Supervisors have a central vantage point to manage the entire operation. In a straight-through configuration, operations are process-centric, with multiple operators located at different machine stations along the length of the line. Operators and packaging components are staged on one side of the line. Regardless of the line layout, material and personnel flows must be properly designed to avoid mix-ups.
SYSTEMS REQUIREMENTS
HVAC
The packaging and warehouse facility designer must be familiar with industrial HVAC, as defined in various documents by the American Society of Heating, Refrigerating, and Air-Conditioning Engineers (ASHRAE) and the American Conference of Governmental Industrial Hygienists (ACGIH). Knowledge of local construction codes, National Fire Protection Association (NFPA) standards, environmental regulations, and OSHA regulations is also assumed. The HVAC system must comply with these and all applicable building, safety, hygiene, and environmental regulations. The design of the HVAC system should consider critical parameters, product exposure, and processes.
Critical parameters for the room environment, which are those that could potentially present a high risk to product quality and patient safety, may include temperature, humidity, and viable and nonviable airborne contaminants, depending on the application. Contamination from viable particles may be a particular risk if an exposed product has microbial limits. Space lighting levels may be a critical parameter, depending on product sensitivity. Room volume air changes and room pressure may be critical parameters when handling exposed products or materials with defined exposure limits. The relative direction of airflow between spaces may be a critical parameter if airborne particles or vapors could have a detrimental effect on product or material in an adjacent space [4].
The classification of product exposure is an important consideration in the design and specification of the HVAC system. The level of protection required must consider if the air is being supplied for exposed or nonexposed product. Operating ranges should be considered in establishing design criteria. The concepts of alert and action points also apply to HVAC monitoring systems. To satisfy cGMP regulations, critical parameters should be monitored, alarmed, and recorded [4].
Room Temperature
Room temperature may be a critical parameter for both open and closed operations. Most products, materials, and processes can handle a wide range in temperatures. However, the width of this range decreases as the exposure time increases. Product stability and personnel comfort must be considered in establishing room temperature requirements. Product requirements are often defined by controlled room temperature, as defined by the United States Pharmacopoeia (USP) General Notices and Requirements [5]: “a temperature maintained thermostatically that encompasses the usual and customary working environment of 68°F to 77°F (20°C to 25°C), that results in a mean kinetic temperature calculated to be not more than 77°F (25°C), and that allows for excursions between 59°F and 86°F (15°C and 30°C) [found] in pharmacies, hospitals, and warehouses.” Provided the mean kinetic temperature remains in the allowed range, transient spikes up to 104°F (40°C) are permitted provided they do not exceed 24 h. Articles may be labeled for storage at controlled room temperature or up to 77°F (25°C), or other wording based on the same mean kinetic temperature. The mean kinetic temperature is a calculated value that may be used as an isothermic storage temperature that simulates the nonisothermal effects of storage temperature variations. Specifying tighter requirements than those actually required will result in a system that is more expensive to purchase and maintain.
Relative Humidity
Room relative humidity may affect exposed product or materials that are sensitive to water vapor. Relative humidity levels generally have negligible effects on sealed containers or aqueous product; however, liquid product can lose moisture to a low-humidity room over an extended period of time. Relative humidity levels can also affect equipment and product storage. Typically, if there are no specific product requirements, humidity is controlled between 30% and 55% relative humidity. This range is selected based on increased problems with static electricity at levels lower than 25% and the increased potential for mold growth at levels greater than 60%. Wide variations in relative humidity in packaging facilities can affect equipment operations and throughput due to changes in material characteristics. It should be noted that specifying tighter requirements than those actually required will not necessarily result in a better-designed HVAC system, but will generally result in a system that is more expensive to purchase and maintain.
Care should be taken with equipment selection, whether for humidification or dehumidification purposes, to ensure that it does not promote microbiological contamination or provide a potential breeding ground for microbiological contamination. If humidification is needed, boiler water additives should not make breathing air unsafe, in conformance with ASHRAE 62 indoor air quality (IAQ) guidelines and any locally applicable codes. Site steam may be used for humidification; clean steam or pure steam is not necessarily required. Boiler water additives (e.g., chelating agents) should not be used, as they can make occupant breathing air unsafe. Products may be sensitive to boiler additives (see the “Site Steam and Condensate” section below).
If dehumidification is provided, the system selected should not have the potential to contaminate the product adversely. Cooling coil-type systems generate large amounts of condensate that must be drained properly and cleaned periodically to avoid microbial contamination. Liquid and dry desiccant systems should be evaluated for potential carryover of desiccant into the supply air system and its effect on the exposed product.
If relative humidity control is required, the boundary of the space to be controlled should be analyzed for potential moisture ingress, through air movement or moisture migration. Vapor barriers or construction materials having low-moisture permeability should be considered.
Airborne Contaminants
The requirements for filtration of air supply depend on the level of protection, but as a minimum should meet ASHRAE 62.2 for IAQ [6]. In nonexposed product areas, no air filtration is required. Air filtration is recommended to protect coils in air handling units (AHUs), both for occupants and to facilitate housekeeping. A minimum of MERV 8 (30% ASHRAE dust-spot efficiency/EN 779 G4) filtration is suggested; however, some sites may need higher filter efficiency and dust-holding capacity as a result of natural local airborne materials, such as pollen, coal, quarry dust, and a combustion exhaust particulates, or to meet ASHRAE 62.2.
In exposed product areas, a minimum of MERV 12 (85% ASHRAE dust-spot efficiency/EN 779 F8) filters is recommended. If air is returned to the HVAC system, a minimum of an H13 (per EN 1822) high-efficiency particulate air (HEPA)–grade filter in the supply or return duct system normally provides adequate protection against cross-contamination between exposed products and materials. If the HEPA filter is critical to deterring cross-contamination, it should be regularly leak tested (see ISO 14644-3), monitored, repaired, or replaced, as required [7]. The area is typically monitored periodically to confirm satisfactory performance. If a failure of the primary HEPA filter would jeopardize product integrity or potent compounds are present, a secondary in-line HEPA filter should be considered; however, HEPA filtration is not adequate for airstreams carrying hazardous or detrimental vapors. It should be noted that an H13-grade filter will not necessarily be suitable for a full-face leak test (ISO 14644-3 B6.2.5), unless it is specified as requiring one [7]. An H14-grade filter is normally suitable for a full-face leak test (ISO 14644-3 B6.2.5), but will typically have a slightly higher pressure drop [7]. Where a HEPA filter is used to control contamination, filter changing during routine or unexpected maintenance should be considered for contamination control. Where potent compounds are present, a safe change or “bag in–bag out” system may be required.
Although there are no airborne particulate classification requirements for packaging and warehouse facilities, such as those that exist for aseptic processing, the design of primary packaging areas should be treated similarly to the last stage of manufacturing. There is no requirement to validate these spaces to this level of cleanliness. Sampling and weighing facilities within a packaging facility require qualification to a standard matching the related manufacturing area. If it requires grade 8 (ISO 8, 0.5 μm particle size) at rest, cleanliness levels have been successfully achieved with 95% dispersed oil particulate (DOP) (MERV 16/EN 1822 H11) filter banks installed in the AHU. The use of terminal HEPA filters is not normally a regulatory requirement, but they may be used where there is exposed product.
If HEPA filters are used on the supply air system, periodic testing is recommended to confirm installation integrity. This testing, generally, can be the total penetration method (i.e., scan testing of the entire filter face would not normally be required). An alternative approach would be routine monitoring of the supply air particle count. Provision of permanent test connections in the air handling equipment or ductwork may be considered. Typically, the testing may be on an annual basis supported by a visual inspection of the filter for damage every 6 months.
In a facility where multiple products are exposed concurrently, dedicated air handlers and ductwork may be more practical and cost-effective than filtration of return air or the use of once-through air. Capital costs will be higher, but filter maintenance and ongoing testing costs should be lower. The efficiency of the chosen air filtration should reflect the potential for cross-contamination as determined by a formal assessment of the risk to product quality and patient safety.
Contamination can originate from both the internal and external environment. In all air handling systems, the filtration should be evaluated for adequate arrest of external particulates. In recirculation systems, the filtration should be specified based on the risk of cross-contamination of product and level of control of both recirculated and incoming particulates. For exposed product areas, if the facility is multiproduct and some of the products have no cross-contamination tolerance with other products, air should not be returned (even if HEPA filtered). A once-through system may be required. Although microbiological control is not normally a consideration, if air intakes are downwind from a high-density source of organisms (e.g., waste treatment facilities), microbial control filtration (e.g., HEPA) may be appropriate.
Relative Pressure
Room relative pressure may be a critical parameter if product is exposed and if it is in a multiproduct building, where some or all products are in dry form, exposed to room air without barriers or capture, or can become airborne and migrate to other product areas. The same applies for products in vapor form where vapor migration could have a detrimental effect on other products or materials.
If airborne concentrations of product, materials, or contaminants are high enough to pose an exposure threat to operating personnel, then air relative pressure may be an issue. When this occurs, both personnel and products exposed in the facility could be at risk. Adjacent spaces are uncontrolled, so that airborne migration of particles in either direction is possible, presenting the risk of cross-contamination. It is also a common practice to maintain a building at slightly positive pressure to minimize the potential for ingress of external particulates, by keeping the supply air volume slightly greater than the extract volume.
While there are no quantified requirements for relative pressurization, in a packaging and warehousing facility, typical design and operational pressure differentials of about 0.02 or 0.03 in. water gauge (wg) are specified. The velocity and direction of airflow between spaces should be adequate to prevent counterflow of airborne particulates or vapor contaminants for spaces where airborne cross-contamination is a concern. Relative pressure gradients should be designed to prevent airborne particulates from passing from a given primary packaging space to an adjacent primary packaging space or from passing from any other adjacent space into primary packaging spaces.
Airlocks or buffer zones are often used to separate production areas from adjacent common corridor and staging areas, noncontrolled areas, and potent drug manufacturing areas. To provide protection, when the doors are closed, positive or negative pressure differentials should be monitored. Time-delay interlocks or alarms that operate if both doors are open simultaneously may be used for added control. Consideration should be given to an emergency override capability when such interlocks are employed. Pressured airlocks may have either positive or negative relative pressure, depending on the situation.
Airflow variations from dust collecting, vacuum, or process systems and their effect on pressurization must be considered in the design and operation of the HVAC system. Before air balancing, rooms should be inspected for obvious leakage paths and architectural integrity, which may have a significant effect on the room air-balance requirements (and associated operating costs), the maintenance of differential pressure, or the ability of particulates to enter or leave the space. Routine monitoring, maintenance, and calibration or air pressure differential devices should be established.
Systems Design Criteria
Table 18.1 provides typical systems design criteria for an HVAC system in a packaging and warehouse facility. Specific product requirements may alter these criteria. In general, the temperature and humidity criteria are provided to satisfy personnel comfort.
Air-Change Rates
Air-change rates are defined as the number of theoretical times the air in a room changes based on the supply air volume and the room volume (less any significant fixed equipment). The exhaust air volume also may be used for this calculation if the room is kept at negative pressure. There is no regulatory requirement for the rate of air changes per hour (ACH).
TABLE 18.1
Typical System Design Criteria
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