1. Purpose
The purpose of this Guideline is to provide a robust logic and guidance document to: Assist in the evaluation of actions required in the design, construction and operation of Packing Facilities. Assist in the clarification of health/hygiene and Good Manufacturing Practice (GMP) issues Be used as a tool to assist in the selection of equipment and facilities for packing operations. Encourage the use of the risk assessment model when considering both health and hygiene and GMP. Assign products to the most appropriate facilities (asset accommodation). Be used as a tool to encourage a consistent, rational, and defensible approach to decisions affecting the design of packing facilities and sitting of packing activities. The application of a consistent and rational approach to facility design and operation is required and is of benefit to the business. However, it is recognized that the derivation of a single approach that can be applied anywhere is not practicable.
2. Scope
This guideline is designed to assist decisions on how to appropriately accommodate the packing of solid dosage forms starting from bulk-packed tablet product through to the finished pack for shipping. The focus of this document is on the technical issues that must be addressed.
3. Definitions
3.1 Beta-Lactams
A major class of antibiotics that includes pencillins, cephalosporins and carbapenems.
3.2 Cleaning Validation
Establishing documented evidence that a specified cleaning procedure will provide a high degree of assurance that it can be used to consistently clean a piece of equipment or a facility to a predetermined acceptable level of cleanliness.
3.3 Containment
The action of confining a chemical entity within a defined space.
3.4 Primary containment
A system of containment, which prevents the escape of a chemical entity into the immediate working environment.
It involves the use of closed containers or safety cabinets along with secure operating procedures.
3.5 Secondary containment
A system of containment, which prevents the escape of a chemical entity from a system of primary containment into the external environment or into other working areas. It involves the use of localized extract booths or rooms with specially designed air handling, the existence of airlocks and secure operating procedures. In many cases it may add to the effectiveness of primary containment.
3.6 Critical Effect
This is the first significant adverse effect(s), which occurs as the dose increases from zero. It is determined after consideration of all the available data. For pharmacologically active compounds, the critical effect may be the pharmacological effect but this is not necessarily the case.
3.7 Cytotoxic
A substance that kills or damages cells if the exposure is high enough.
3.8 GMP
Good Manufacturing Practice
3.9 Hazard (toxic)
Any substance, which has the potential to cause harm to people.
3.10 HEPA – Filter (High Efficiency Particulate Air Filter)
Filter classification system based on nominal retention rate expressed as % of particles retained > 0.5µm, e.g. EU10: 95-99.9%; EU13:99.99-99.999%
3.11 HVAC (Heating, Ventilation, Air Conditioning)
The provision and handling of controlled conditioned air to processing and service rooms. The conditions shall include control of temperature, humidity, filtration, quality and room pressures.
3.12 LD50 value
The LD50 (Lethal Dose, 50%) value is typically expressed in mg of material per kg of subject-body-weight, and indicates the quantity of material that, if administered to a population of subjects, will cause 50% of the subjects to perish.
3.13 Local Exhaust/Extract System
Consists of a control exhaust hood, duct work, exhaust, filter and controls used to control an air contaminant by collecting it at source. A local hood/booth is the point of entry of air to the system.
3.14 Material Safety Data Sheet
A Material Safety Data Sheet provides information on the hazards to health, safety and environment inherent in a chemical substance.
3.15 Minimal Effect Dose
Based on animal / human data, the minimum dose at which measurable (pharmacological, pharmacodynamic, clinical) effects have been observed in man.
3.16 Nil Effect Dose
Based on human data, the maximum (single or repeated) dose at which no measurable (pharmacological, pharmacodynamic, clinical) effects have been observed in man.
3.17 Occupational Exposure Limit (OEL)
The OEL is a criterion/standard used to determine what is required to control employee exposure to a substance.
3.18 Occupational Hygiene
Occupational hygiene practice is the application of principles to ensure adequate control of exposure to hazards and to minimize the risk in the workplace to adverse health effects.
3.19 Occupational Hygiene Monitoring (OHM)
Occupational hygiene monitoring is the measurement of airborne substances in the workplace to assess potential for exposure and assess effectiveness of controls.
3.20 Packing Bay
This is the area within a packing facility that houses the group of equipment that make up the packing line, e.g., blister former, labeler, and end of line equipment.
3.21 Packing Facility
The building and services which house the hardware.
3.22 Packing Line
The combination of equipment receiving the bulk formulated product and generating the primary container and may also generate the final pack for shipping.
3.23 Primary Packing
Any material employed in the packaging of a pharmaceutical product, excluding secondary packaging and any outer packaging used for transportation or shipment. Primary packaging material(s) form the container/closure system for the product and therefore may be in direct contact with the product. Examples include HDPE bottles/caps, blister strip packs, tubes/caps for ointments.
3.24 Primary Packing Equipment
The hardware used to put the product into its primary container, e.g., the blister former or bottle filler.
3.25 Personal Protective Equipment (PPE)
Any equipment worn by an operator or technician to minimize exposure to a drug or substance, e.g., to provide protection to hands, eyes, skin or to prevent inhalation.
3.26 Potent
A compound that is biologically active at low doses.
3.27 Pressure Regimes
A subdivision of a series of rooms into defined air pressure regimes. The pressure regimes are cascaded, with the lowest pressure at the point of highest risk of loss of contaminant, to prevent airborne material transmission from process rooms into adjacent transit areas.
3.28 Respiratory Protective Equipment (RPE)
Equipment used as part of the strategy to control personal exposure to the product via the inhalation route.
3.29 Respiratory Sensitizer
A substance that can trigger an allergic reaction in the lungs or airways of a sensitized individual.
3.30 Risk
The combination of the severity of potential consequences, which could arise from a hazard and likelihood that these consequences will be realized.
3.31 Risk Assessment
The process used to evaluate whether or not the level of risk is tolerable. This is a three-step process:
1. Identification of the hazard
2. Assessment of the risks
3. Management of the risks
3.32 Secondary Packing
Secondary packs are not in direct contact with the product. Examples include, cartons used to contain blister packs, corrugated boxes for bottles, cartons for tubes. Secondary packaging components essential to the function or stability of the product, although not in direct contact with the product, should be regarded as primary materials or components.
Examples include blister packages of single dose pipettes (needed for stability), ampoules stated to be sterile on the outside, needle covers of syringes, inks for printing on primary plastic containers, capping for stoppers, desiccant sachets, etc.
3.33 Sensitizer
A substance that can trigger an allergic reaction.
3.34 Toxic
Poisonous; the intrinsic ability of a substance to poison. Used in the EC as a labeling phrase, based on a specific range of LD50 values in animals, reprotoxic, carcinogenic and mutagenic properties. It indicates a substance of high acute toxicity.
3.35 Toxicity
The degree of strength of a poison. The toxicity of a chemical is its ability to cause injury once it reaches a susceptible site on or in the body, e.g., the skin, the brain, the intestinal tract, etc.
3.36 Unit
A room or series of rooms and process equipment.
3.37 WIP (Wash In Place)
Automated or otherwise preliminary cleaning system frequently used to make hazardous materials safe by wetting. Will require further manual or remote automated cleaning to meet the requirements of validated cleaning.
3.38 Zoning
Creation of a zone(s) within a facility inside which secondary containment is maintained so as to prevent contamination of adjoining ones or the external environment by chemical entities from within the zone.
4. Responsibilities
Compliance and Quality Assurance groups are responsible for defining the standards of GMP that are applicable for a particular process.
Site management is responsible for implementing the procedures and practices identified as providing the defined level of GMP and safety protection. Site management is responsible for defining the standards required to effect operator health and safety.
Engineering and site management are responsible for providing facilities and equipment that meet the requirements of GMP, safety and the needs of sourcing and asset strategies.
Manufacturing Strategy Group is responsible for designing strategies for the sourcing of individual products and for the provision of manufacturing assets consistent with the requirements of GMP and Safety.
5. Guideline
Company product portfolio may includes a wide range of active materials. Effective use of those actives requires a clear recognition and understanding of the hazards, how to manage the associated risks and adequately control employee and patient exposure.
Experience has shown that:
Historically there have been significantly different approaches taken to the management of containment and cross contamination reduction.
Uncertainty and lack of clarity regarding requirements can result in inconsistent application of design and operation standards.
A number of common questions affecting accommodation/control decisions have arisen from different areas of the Company.
This has resulted in duplication of effort and the potential for application of inconsistent solutions.
Decisions affecting packing operations have sometimes been based on hazard or perceived hazard, rather than risk.
A specific example is products in the class “cytotoxic”. Whilst all products in this class “kill cells”, the mechanism of action and specific properties of individual products in this class may be different, and may require different solutions to accommodate them.
Decisions affecting packing operations have sometimes been taken based on an inconsistent interpretation of GMP guidelines.
Key factors affecting the design and operation of packing facilities and equipment (existing or new) should include:
– Operator protection
– Environmental protection
– Protection of patients in the community
– Product associated hazard and risk
– Company standards
– Engineering standards
– Packing engineering technology options
A project team with representatives from Manufacturing Strategy Group, Safety management, Engineering,
GMP Compliance should be set up to identify the key issues and how to address them.
The main issues affecting the company are:
– For a multi product company, aims should be to build flexible multi-product facilities.
– Need to provide and use Company assets in a cost-effective way whilst maintaining the license to operate.
– Different design solutions carry different costs.
– Design decisions do not always take a rational and consistent view of regulatory issues (health/hygiene/GMP).
– Lack of clarity around the relative importance of hygiene, GMP, and engineering issues leading to inconsistent/inappropriate design and operational decisions.
– Decisions have sometimes been made on the basis of hazard, or perceived hazard, rather than risk
5.2 Methodology
Good occupational hygiene practice aims to protect employees in the workplace and GMP is directed, ultimately, more towards protection of the patient in the community. Consideration of design decisions and equipment selection may be clarified by reviewing the hygiene and GMP issues separately. Use of this approach is based on few assumptions:
– Hygiene issues are relevant as soon a product is handled in the workplace.
– GMP issues become relevant as soon as the product is manufactured for use in man.
– GMP issues become more complex as the scale increases and/or when facilities are used to produce more than one product.
The approach to making design decisions should use four steps:
1. Clearly establish:
a) Hygiene and then
b) GMP issue
2. Review the options to meet:
a) Hygiene and then
b) GMP needs
3. Consider the options and develop solutions that meet the needs of both hygiene and GMP.
4. Review design and operational options.
The logic diagram (See Appendix 1) provides a pathway to follow in the development of design decisions for packing facilities and packing equipment. The left hand side of the diagram addresses health and hygiene issues and the right hand side addresses GMP issues.
Some users of this guidance may choose to read some but not all of the supplementary text. Therefore, where relevant some technical advice may be repeated in more than one section.
5.3 Health and Hygiene
The sub-sections below follow the health and hygiene logic diagram, i.e., the left hand side of the diagram as shown in Section 6.1 Appendix 1.
5.3.1 Critical Effect
The critical effect is the first or most significant adverse effect encountered on exposure to a chemical. The critical effect is determined after consideration of all the relevant information and is used in the Occupational Exposure Limit (OEL) setting process.
– A no-effect dose or low effect dose is established for the critical effect
– Uncertainty factors are applied
– All judgments are made on a case-by-case basis
– Where there is a gender specific effect, the OEL derived for this effect will be applied for both sexes.
– Segregation will be avoided.
5.3.2 Determine the OEL
OELs are specific to the active ingredient and are agreed by a panel of experts (Toxicology and Regulatory Group Manager, Clinical Occupational Health Representative, Occupational Hygiene Representative, Manufacturing Department Representative, Occupational Toxicology Manager and Co-opted members form R&D).
5.3.3 Review hazard information
The material safety data sheets (MSDS) provide a summary of information about the hazards of the material.
One section of the safety data sheet gives the OEL. The hazard is the potential of the material to cause harm.
5.3.4 Additional hazard Information
In some cases there may be additional information about the hazard that requires further advice from occupational health professionals to assist decision makers, e.g., potent skin sensitizer.
5.3.5 Assess risk of exposure to the “hazard” in local operation.
The risk is the combination of the severity of the potential consequences, which could arise from a hazard and the likelihood that these consequences will be realized in the circumstances of use.
It is very important to make a clear distinction between “hazard” and “risk”. Experience has shown many examples of decisions affecting operations being based on hazard or perceived hazard, rather than risk. These are an issue for the company.
Risk assessment and risk management is a three-step process (see Figure 1).
Figure 1: Three-step model for risk assessment
5.3.6 Examples of factors affecting risk of exposure in tablet packing
There are many factors that can affect the potential for exposure in workplace environments.
In general the potential for exposure during routine packing operations should be low if equipment is well maintained and appropriate procedures are followed.
A key factor in the control of exposure in tablet packing is whether the tablet is uncoated or coated.
The Company product development policy recommends application of a film coat to all tableted products.
Both the potential for spillage and spread of contamination should also be low if the principles outlined here are applied. Spillage should be considered in the risk assessment and the actions required in the event of a spill should be clearly specified in operational procedures.
5.3.7 Can exposure be controlled to the OEL?
OELs can be used as tools in risk management. OELs are health-based standards which are used to help decide what actions are necessary to control personal exposure to airborne substances at work. In many cases experience and the risk assessment provides the information to give reassurance that adequate control of exposure of substances has been achieved.
If there are uncertainties about compliance with the OEL there are tools to help, e.g., Occupational hygiene monitoring of airborne concentrations. This should be done using the appropriate validated sampling and analytical methodology and occupational hygiene monitoring strategy.
Whilst risk assessment must be carried out locally to determine the potential for exposure, in general, the nature of packing activities is such that there should not be significant potential for airborne exposure if all operational controls are robust.
The OEL relates to exposure via inhalation. Where relevant, the potential for exposure via all routes should be considered, e.g., inhalation, ingestion, skin.
5.3.8 Can engineering designs achieve this OEL without PPE?
It is Company policy and a legal requirement in many of the Countries in which we operate that personal exposure must be controlled by means other than PPE, i.e., routine use of PPE is the last resort.
The rationale for this is sound and takes account of many factors, e.g.:
– Use of PPE does not prevent the spread of contamination
– The user may potentially be exposed when PPE is removed
– Other operators in the workplace who are not using PPE may be exposed.
The primary disadvantage to PPE is that is does not eliminate the hazard from the workplace and if it were to fail it results in exposure to the hazard.
Although the use of PPE should be considered the last resort for routine operation its use may be appropriate for some tasks, e.g., non-routine equipment maintenance or emergency responses to spills. The successful use of PPE relies on the equipment being properly chosen, used, cleaned, stored, and maintained. Operators have to be trained in its use.
5.3.9 Choose the appropriate technology to minimize the use of PPE
In solids handling, gloves and Respiratory Protective Equipment (RPE) are typically the most common type of PPE.
In general, there are four situations where the use of PPE is useful and appropriate.
– When it is not technically feasible to control exposure by other means.
– For emergency procedures such as cleaning major spillages.
– For maintenance work where containment is breached.
– Where the risk assessment has shown an immediate risk that needs control until other means of control can be specified, installed, and effectiveness validated.
The inherent nature of well-designed and appropriately used packing equipment is such that the routine use of PPE such as respiratory protective equipment (RPE) should rarely be necessary. The risk assessments for spillage and maintenance activities may identify the need to use PPE. Again, in the case of packing operations, it should be possible to prevent or minimize the routine use of RPE. If PPE is required the key factors to consider in the choice of PPE are the:
– Task
– Hazard/contaminant
– Environment and
– User
For example, there are many alternative types of RPE. If the risk assessment identifies the need for RPE use for any activity associated with packing it is more likely to be an air-purifying respirator, e.g., a negative-pressure respirator, that relies on the user’s breathing to pull air through a filter, rather than positive-pressure supplied air equipment, e.g., air-fed hoods.
The local risk assessment should include an assessment of the need for PPE and where it is decided it is required, the specific details should be recorded, e.g., the type of RPE.
5.3.10 Can a cost-effective technology solution be found?
Engineering containment technology is of primary importance. This will need to be supported by administrative controls, good training in their use etc.
Begin with the end in mind! The equipment should be designed to meet Company packing and Safety needs, as retro-fit of engineering controls is expensive and, in some cases, may not be possible. Engineering controls must be integrated with the process.
Occupational exposure limits provide the basis of the design goal for containment (for the purpose of controlling exposure to personnel in the workplace).
There is a hierarchy of technologies for engineering containment, i.e., in order of preference:
– Enclosure
– Controlled airflow, e.g., laminar airflow
– Local exhaust
– Open systems
Well-designed containment systems reduce the potential for cross-contamination and encourage the use of good standard operating procedures.
The choice must be cost-effective, i.e., the most expensive option is not necessarily the best and a range of technologies may meet the goal. A review of the relative cost implications of each should be carried out.
In the case of packing activities it should be possible to find cost-effective technology solutions to contain the product.
5.4 Good Manufacturing Practice (GMP)
The sub-sections below follow the GMP logic diagram, i.e., the right-hand side of the diagram as shown in Appendix 6.1.
There are many issues to be considered when reviewing GMP requirements in deciding the appropriate containment technology to be adopted. In some cases the accommodation of the product is driven by clear GMP requirements.
Most cases are not that clear-cut and a variety of options have to be considered. These questions are considered below and should be used to follow the GMP decision tree in Appendix 6.1.
5.4.1 Is it a GMP requirement to handle the product in a dedicated facility?
The GMPs may require that a separate facility be used for a particular compound. The most obvious situation is the beta-Lactam class of antibiotics where the various GMPs [EU section 5.19(a) and US section 211.42(d)] require separate facilities for the manufacture, processing and primary packing of beta-Lactams.
The decision to handle a product in a separate facility may be based on negotiations with one or more regulatory agencies.
In this case it is not clearly stated in any particular GMP regulation but it is rather the opinion of the agency that current GMP (cGMP) requires either partial or complete isolation of a production process.
Another example where a decision to use a dedicated facility might be made would be based on the evidence of an unacceptable risk as deemed by company. This covers agents that are not directly identified in a written GMP document but that our knowledge of the compound leads us to decide that the potential risk of cross-contamination far exceeds the benefits of being able to use multi-product facilities.
5.4.2 Obtain cleaning validation criteria
Proper utilization of equipment and facilities requires knowledge of the potential for carryover of one product into another. This is a characteristic based on the chemical and physical nature of the compound and the design and materials of construction of the equipment and/or facility. The acceptable level of carryover can be determined through a number of methods. Some of the more common criteria include:
– Not more than 10 ppm of Product A carried over to Product B
– Nil Effect Dose/Minimum Effective Dose
– Visibly clean
The criteria selected will usually be one, or a combination, of A, B or C. Visibly clean is always part of the criteria, as this is required by GMP regulations.
It is possible that no safe level of product carryover can be determined. A classic example of this is penicillin.
Other compounds may have a toxicity profile that dictates the use of dedicated equipment and/or a dedicated unit or facility.
5.4.3 Can cleaning be carried out to meet the required criteria?
The following points need to be considered:
1) Feasibility: Is it possible to clean the equipment to meet the required level of detection? Can validation be accomplished through the use of swab testing, rinsing samples, or both? Is there an analytical method that can detect the required level of sensitivity?
2) Practical: Is the effort required to perform the cleaning operation practical?
What effort is required to perform the cleaning, e.g., number of personnel required, does the facility have to be shut down, is there an operator exposure risk, what chemicals are required to perform the cleaning (environmental considerations)?
3) Cost: What is the cost associated with performing the cleaning operation?
What are the direct and indirect labour costs? If the plant has to be shut down what are the product supply considerations? Are expensive cleaning chemicals required? Is there a significant waste disposal cost?
5.4.4 Are there any other GMP factors that could prevent the use of a multi-product facility?
Other GMP factors to take into account when considering whether or not a particular facility is appropriate for the product under review might be:
1) Facility Standards: The facility itself might not meet the appropriate standards to permit manufacturing with no restrictions. An example might be the differential pressure values and direction of airflows are not adequate to control cross-contamination.
2) Operational Standards: is the facility being operated to a standard that permits the handling of the product under consideration? Is specialist knowledge required?
Do the operators need to have specialist training prior to handling the product? Is containment handled viaengineering controls or are procedural controls used and are these adequate?
3) Cross-contamination arising from Secondary Packaging: The potential for ‘cross-contamination’ during the secondary packing operation is a cosmetic issue and is not regarded as significant from a GMP point of view, e.g., contamination of primary packed product with secondary packing material, e.g., cartons, cardboard. In some countries (e.g., Japan) protection of exposed tablets is required and therefore where local regulatory requirements dictate this, they should be provided. Therefore, for oral solid dosage products there is normally no need to separate primary packing from secondary packing.
5.4.5 Can the GMP issues be resolved?
If the answers to 1 and 2 above are they can be satisfactorily resolved then the use of a multi-product facility can be further considered. If the answer is No, then consider 5.4.6.
5.4.6 The product may be accommodated in a multi-product facility with dedicated equipment or units
The following options may allow accommodation within a multi-product facility:
1) Separate Unit: Dedicating a defined manufacturing unit within a multi-product facility is another option to address cleaning and/or other GMP aspects unique to a particular product. For example, a product that is difficult to clean may be acceptably handled within a separate unit within a multi-product facility.
Consider the use of differential pressure regimes to minimize the possibility of cross-contamination.
2) Dedicated Equipment: Dedicating equipment for a particular step, e.g., changing parts, may address issues regarding the feasibility of cleaning or concerns over cross-contamination.
3) Dedicated Line: Certain product classifications, e.g., beta-Lactams, may dictate the use of a dedicated line.
5.4.7 Can the cleaning criteria be met for some stages of the packing operation?
It is possible that parts of the process may be sufficiently easy to clean that the cleaning validation criteria can be met.
This could lead to a hybrid situation whereby part of the equipment, or an individual line or unit, may be dedicated but
other unit(s) or pieces of equipment are acceptable for multi-product use. If the answer is No then the logic confirms the use of a single product facility.
5.4.8 Can the contaminated equipment be isolated to prevent cross contamination of other parts of the facility?
In connection with the step above, and if the contaminated equipment or unit can be isolated to prevent cross-contamination, then it will be possible to review the options for placing the product into a multi-product facility with dedicated equipment, line and/or units.
5.4.9 The product can only be accommodated in a single product facility
This is the least flexible option regarding facility use but demands of operator protection, cleaning and GMP may dictate its use.
6. Appendices
6.1 Appendix 1 Logic Diagram to enable packing decisions using both Health / Hygiene and GMP / Regulatory data
6.2 Engineering and Operational Factors to Consider in the Design
6.2.1 Segregation of Packing Lines
The most important factor to concentrate on is the flow of materials around the packing bay itself in order to avoid mix-ups or cross-overs of one product or product component with another. Normally there is no need to segregate primary oral solid dosage packing from secondary packing, but it is essential that demarcation barriers be provided around individual lines and an adequate working space to ensure good materials flow, segregation and storage.
An acceptable standard to avoid uncontrolled movement of materials is to segregate the packing bays by a barrier. The barrier should be high enough to prevent transfer between packing bays, e.g., 2 meters.
The barrier must be solid and sealed at floor level between adjacent packing bays. Although it is not essential there is a trend towards providing cubicle enclosures around the primary packing operation where the product is enclosed and sealed in the primary pack.
This arrangement has the advantage of providing enhanced protection against product cross contamination. It also offers the possibility of capital cost saving on the facility by having relatively high facility standards within the cubicle and lower facility standards in the secondary packing area.
A possible layout and arrangement is provided for guidance in Diagrams 1 and 2.
6.2.2 Heating, Ventilation and Air Conditioning (HVAC)
The provision of HVAC for primary packing would normally incorporate temperature control (18-250C) and humidity control for operator comfort. These are not quality-critical parameters unless there are product-specific requirements.
For moisture-sensitive products where a lower humidity is required, e.g., 30-50% then localized at line control should be considered first rather than controlling the entire packing facility environment. Air changes should be provided to ensure operator comfort and heat removal but should not be less than five per hour; again, this is not a quality-critical parameter.
Re-circulated air is preferred for reason of energy efficiency. Typically 90% of the air is re-circulated with 10% fresh air make-up. In primary packing areas where product is exposed air should be filtered to grade EN1822 H10. Where product is exposed and air is re-circulated two stages of H10 filtration should be provided for the re-circulated air to ensure no product cross-contamination.
This is best done by providing H10 filtration at the point of air extract from the room or area to prevent contamination of the ductwork system and at the supply from the air-handling unit serving the room or area.
For secondary packing air filtration to EN779 F9 is considered adequate. The design standard for HVAC particulate quality where product is exposed and for a new or substantially refurbished packing hall should be to European Grade D (class 100,000 at rest).
Post-commissioning routine environmental monitoring is not a requirement for packing halls.
Any environmental monitoring performed is a local decision.
The HVAC system should effectively sweep the air in the facility, e.g.:
a) Entry at one side of the facility extract on the opposite side, longitudinal sweep
b) Entry at a high level in the center of facility and extract at the perimeter at a high level
c) Entry at ceiling level and extract at floor level.
It should be noted that there is no requirement for a dedicated air supply to each separate packing bay. For secondary packing (i.e., after the product has been sealed in the blister or bottle) there are no regulatory requirements in regard to HVAC quality, but commonly the same standard is used throughout the packing facility because they are often supplied from the same system.
The provision of cubicles around the primary packing area allows a lower standard of ventilation air to be provided to the secondary packing area. Additional general comments on HVAC in packing halls:
(i) Packing line machinery often generates a great deal of heat and along with high-intensity lighting and the relatively large numbers of operators, there is often a need to have greater than 5 air changes/hour to deal with the heat gain.
(ii) It should be noted that modern blister packing lines are usually enclosed with Perspex doors etc, so airflows over packing lines do not necessarily sweep directly over the exposed product.
6.2.3 Space Requirements for Packing
There should be sufficient space allocated to a packing line bay to allow the controlled movement of materials too and from the line. The space in the bay should allow for GMP checks on materials to be carried out within the bay. For a fully automatic and straight blister packing line (non-wallet) a typical packing bay size is 27m long and between 6 and 7m wide. This allows space for primary and secondary packing equipment.
6.2.4 Wall and Ceiling Finishes
Wall and ceiling finishes must be of a standard such that contamination is reduced to a minimum, e.g., in primary packing areas proprietary factory steel partitioning or plaster and painted blockwork. In secondary packing areas, a pharmaceutical warehouse finish standard can be adopted.
6.2.5 Floor Finishes
Floor finishes should allow easy cleaning, e.g., coved finishes in primary packing areas. A number of different floor finishes can be considered which are consistent with the usage and standard of cleanliness required, e.g., vinyl, resin, resin terrazzo, sealed concrete, etc.
6.2.6 Packing Facility Operation:
Temperature, humidity, air flows and pressure differentials There are no general regulatory requirements for the monitoring of temperature, humidity within a packing facility.
It is likely that these will be monitored at a frequency for operational control of the HVAC system. There may be, as a result of a specific product requirement of monitor and record humidity and temperature. This should be carried out up to the point where the product is being sealed into the primary container, e.g., a moisture-sensitive product is likely to have local control of humidity and this will be monitored from the tablet hopper to the tablet being sealed it the primary container.
Generally, the packing hall should be at a positive pressure to ambient to give air flows from the packing hall to the outside and into technical spaces and be negative with respect to surrounding corridors to give air flows from the corridors into the packing facility.
Air flows from primary packing cubicles, if provided, should cascade out into the general packing space unless there is a concern to contain particular products, in which case the direction of airflow should be into the cubicle, or the cubicles provided with an effective airlock.