Who Guidelines On Gmp Hvac (rev1) 3qi6r

WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE

Working document QAS/02.048/Rev.1 RESTRICTED

SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR CONDITIONING (HVAC) SYSTEMS FOR NON-STERILE DOSAGE FORMS

This document has been prepared by Mr Deryck Smith of Deryck Smith Consulting Engineers, Faerie Glen, South Africa as a supplementary WHO Good Manufacturing Practices (GMP) text for Heating, Ventilation and Air Conditioning (HVAC) Systems. It is built on the existing WHO GMP texts, and makes use of auxiliary documents and manuals as listed in the reference section. Comments received during the first consultation phase have been evaluated and the text has been revised accordingly. Please address any comments and/or corrections you may have on this document to Dr S. Kopp, Quality Assurance and Safety: Medicines, Essential Drugs and Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland, fax: (+41 22) 791 4730 or e-mail:[email protected], by 15 December 2004.

© World Health Organization 2004 All rights reserved. This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations’ concerned staff and member organizations) without the permission of WHO. The draft should not be displayed on any website. Please send any request for permission to: Dr Sabine Kopp, Quality Assurance & Safety: Medicines (QSM), Department of Essential Drugs and Medicines Policy (EDM), World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; e-mails: [email protected] The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The World Health Organization does not warrant that the information contained in this draft is complete and correct and shall not be liable for any damages incurred as a result of its use.

Working document QAS/02.048/Rev.1 page 2

SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR CONDITIONING (HVAC) SYSTEMS FOR NON-STERILE DOSAGE FORMS

CONTENTS

page

1. 2. 3. 4.

Introduction ……………………………………………………………………………….. Glossary …………………………………………………………………………………… Scope of document ………………………………………………………………………... Product protection …………………………………………………………………………

3 4 8 9

4.1 Contamination control ………………………………………………………………

9

Cleanroom concept …………………………………………………………. Level of protection ………………………………………………………….. Air filtration to control contamination ……………………………………… Contamination by HVAC plant …………………………………………….. Contamination by staff ……………………………………………………… Airflow patterns …………………………………………………………….. Unidirectional Airflow (UDAF) protection …………………………... Infiltration ……………………………………………………………………

10 16 17 19 19 19 23 24

4.1.1 4.1.2 4.1.3 4.1.4 4.1.5 4.1.6 4.1.7 4.1.8

4.2 Cross-contamination protection …………………………………………………….. .25 4.2.1 Directional air movement …………………………………………………… .25 4.2.1.1 4.2.1.2 4.2.1.3 4.2.1.4

Displacement concept ……………………………………………… 25 Pressure differential concept ………………………………………. 26 Physical barrier concept …………………………………………… 30 Selecting the segregation concept …………………………………. 30

4.2.2 Unidirectional Airflow protection ………………………………………… 30 4.2.3 Cross-contamination via HVAC supply air …………………………………. 30 4.2.4 Cross-contamination due to fan failure ……………………………………… 31 4.3

Temperature and Humidity …………………………………………………………. 31 4.3.1 4.3.2 4.3.3 4.3.4

5.

General temperature and humidity requirements …………………………… 31 Product temperature requirements ………………………………………….. 31 Product humidity requirements ……………………………………………... 31 Microbial growth …………………………………………………………….. 33

Personnel Protection ………………………………………………………………………. 33 5.1 5.2 5.3 5.4 5.5 5.6 5.7

Protection from dust ………………………………………………………………… Dust classification …………………………………………………………………... Unidirectional flow protection ……………………………………………………… Point extraction ……………………………………………………………………. Directional airflow ………………………………………………………………… Air showers ………………………………………………………………………. Protective enclosures ………………………………………………………………

33 33 33 38 38 39 39

Working document QAS/02.048/Rev.1 page 3

5.8 6.

40

Protection of the Environment …………………………………………………………… 41 6.1 6.2 6.3

7.

Operator comfort …………………………………………………………………..

Exhaust air dust ……………………………………………………………………. 41 Fume removal ……………………………………………………………………… 42 Effluent discharge …………………………………………………………………. 42

Systems and Components ……………………………………………………………….. 7.1 7.2

42

Air distribution …………………………………………………………………….. 42 Air handling unit configurations ………………………………………………….. 44 7.2.1 Recirculation system ………………………………………………………. 44 7.2.2 Full fresh air systems ……………………………………………………… 45 7.2.3 Additional system components ……………………………………………. 46

8.

Commissioning, Validation and Maintenance …………………………………………...

47

Commissioning ……………………………………………………………………. Validation and qualification ……………………………………………………….

47 48

8.1 8.2

8.2.1 Validation master plan (VMP) …………………………………………….. 49 8.3 8.4 8.5 8.6 8.7

What to qualify …………………………………………………………………….. Setting qualification limits …………………………………………………………. Parameters to qualify …………………………………………………………….…. Maintenance ……………………………………………………………………….. Inspections ………………………………………………………………………….

49 50 52 58 59

References ……………………………………………………………………………………… 60

1.

INTRODUCTION

Heating, Ventilation and Air Conditioning (HVAC) play an important role in ensuring the manufacture of quality pharmaceutical products. This guideline mainly relates to HVAC systems for solid dosage pharmaceutical plants. However, reference is often made to other systems or components which are not relevant to solid dosage plants, but it is felt that these references help to provide a comparison between the requirements for solid dosage plants and other systems. HVAC system design influences architectural layouts, with regards to items such as airlock positions, doorways and lobbies. The architectural components have an effect on room pressure differential cascades and cross-contamination control. The prevention of contamination and cross-contamination is an essential design consideration of the HVAC system. Because of these critical aspects, the design of the HVAC system should be considered at the concept design stage of a pharmaceutical manufacturing facility. Temperature, humidity and ventilation should be appropriate and should not adversely affect the pharmaceutical products during their manufacture and storage, or the accurate functioning of equipment. A suitably designed HVAC system assists in ensuring the manufacture of quality products. A well designed HVAC system will also result in operator comfort. This document aims to give guidance to inspectors of pharmaceutical manufacturing facilities, on the design, installation, qualification and maintenance of the HVAC systems.

Working document QAS/02.048/Rev.1 page 4

2.

GLOSSARY

The definitions given below apply to used in this guideline. They may have different meanings in other contexts. Absolute humidity (also termed specific humidity or humidity ratio) The ratio of the mass of water vapour in the air per unit mass of dry air. Expressed in grams/kg or kg/kg. Acceptance criteria Measurable under which a test result will be considered acceptable. Action limit Action limit is reached when the acceptance criteria of a critical parameter have been exceeded. Results outside theses limits will require specified action and investigation. Air Handling Unit (AHU) Air handling unit, which serves to condition the air and provide the required air movement within a facility. Airlock An enclosed space with two or more doors, which is interposed between two or more rooms, e.g. of differing classes of cleanliness, for the purpose of controlling the airflow between those rooms, when they need to be entered. An airlock is designed for, and used, by either people or goods (PAL = Personnel airlock & MAL = Material airlock). Alert limit Alert limit is reached when the normal operating range of a critical parameter has been exceeded, indicating that corrective measures may need be taken to prevent the action limit being reached. API Active pharmaceutical ingredient As-built condition This condition relates to carrying out room classification tests on the bare room without any production equipment or personnel. ASHRAE American Society of Heating, Refrigeration and Air Conditioning Engineers. At-rest condition This condition relates to carrying out room classification tests with the normal production equipment in the room, but not operating and without any operators. Central Air Conditioning Unit An air handling unit which is centrally located and supplies air to a number of rooms. As opposed to a local AHU which supplies air to one room only.

Working document QAS/02.048/Rev.1 page 5

Change control A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure that the system is maintained in a validated state. Cleanroom A room or area with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation and retention of contaminants within the area, and in which other relevant parameters (e.g. temperature, humidity and pressure) are controlled as necessary. Commissioning Commissioning is the documented process of ing that the equipment and systems are installed according to specifications, placing the equipment into active service and ing it’s proper action. Commissioning takes place at the conclusion of project construction but prior to validation. Containment A process or device to contain product, dust or contaminants in one zone, preventing it from escaping to another zone. Contamination The undesired introduction of impurities of a chemical or microbial nature, or of foreign matter, into or on to a starting material or intermediate, during production, sampling, packaging or repackaging, storage or transport. Critical parameter or component A processing parameter (such as temperature or humidity) that affects the quality of a product; or a component that may have a direct impact on the quality of the product. Cross-contamination Contamination of a starting material, intermediate product or finished product with another starting material or material during production. Design condition Design condition relates to the specified range or accuracy of a controlled variable used by the designer as a basis to determine the performance requirements of an engineered system. Design qualification (DQ) DQ is the documented check of planning documents and technical specifications for design conformity with the process, manufacturing, cGMP and regulatory requirements. Direct impact system A system that is expected to have a direct impact on product quality. These systems are designed and commissioned in line with Good Engineering Practice and, in addition, are subject to Qualification Practices. Drug substance Starting materials, such as excipients and active ingredients, used to make up the final pharmaceutical product. ECS Environmental control system, also referred to HVAC

Working document QAS/02.048/Rev.1 page 6

Facility The built environment within which the cleanroom installation and associated controlled environments operate together with their ing infrastructure. Good Engineering Practice (GEP) Established engineering methods and standards that are applied throughout the project lifecycle to deliver appropriate, cost-effective solutions. HEPA filter High Efficiency Particulate Air filter. HVAC Heating Ventilation and Air Conditioning, also referred to Environmental Control System (ECS). Indirect impact system This is a system that is not expected to have a direct impact on product quality, but typically will a direct impact system. These systems are designed and commissioned according to Good Engineering Practice only. Installation qualification (IQ) IQ is documented verification that the premises, HVAC system, ing utilities and equipment have been built and installed in compliance with their approved design specification. ISO 14644-1 An international standard relating to the classification of clean environments. This standard is set to replace all existing national standards such as the US Fed. Std. 209, BSS5295, EEC and DIN. This guideline will make reference to the ISO classifications. A comparison between the various existing standards is given in Chapter 8. ISPE International Society for Pharmaceutical Engineering Laminar airflow Laminar airflow or unidirectional airflow is a rectified airflow over the entire cross-sectional area of a clean zone with a steady velocity and approximately parallel streamlines (see also turbulent flow). (Modern standards no longer refer to laminar flow, but have adopted the term unidirectional airflow) Level of protection The level of protection defines the level of protection required in various zones of the production facility. No impact system This is a system that will not have any impact, either directly or indirectly, on product quality. These systems are designed and commissioned according to Good Engineering Practice only. Non-critical parameter or component A processing parameter or component within a system where the operation, , data control, alarm or failure will have an indirect impact or no impact on the quality of the product.

Working document QAS/02.048/Rev.1 page 7

Normal operating range Normal operating range is the range that the manufacturer selects as the acceptable values for a parameter during normal operations. This range must be within the operating range. Operating limits The minimum and/or maximum values that will ensure that product and safety requirements are met. Operating range Operating range is the range of validated critical parameters within which acceptable products can be manufactured. Operational condition This condition relates to carrying out room classification tests with the normal production process with equipment in operation , and the normal staff present in the room. Operational qualification (OQ) OQ is the documented verification that all aspects of a facility, utility or equipment that can effect product quality, operate as intended through all anticipated ranges. Usually carried out over an extended period to prove ongoing conformance. OSD Oral solid dosage – usually referring to an OSD plant that manufactures medicinal products such as tablets, capsules and powders to be taken orally. Performance qualification (PQ) PQ is the documented verification that the process and/or the total process related to the system, performs as intended throughout all anticipated operating ranges. Pressure cascade A process whereby air flows from the cleanest area, which is maintained at the highest pressure to a less clean area at a lower pressure. Qualification Qualification is the planning, carrying out and recording of tests on equipment and a system, which forms part of the validated process, to demonstrate that it will perform as intended. Relative humidity The ratio of the actual water vapour pressure of the air to the saturated water vapour pressure of the air at the same temperature expressed as a percentage. More simply put, it is the ratio of the mass of moisture in the air, relative to the mass at 100% moisture saturation, at a given temperature. Standard operating procedure (SOP) An authorized written procedure, giving instructions for performing operations, not necessarily specific to a given product or material, but of a more general nature, (e.g. equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documentation. Turbulent flow Turbulent flow, or non-unidirectional airflow, is air distribution that it is introduced into the controlled space and then mixes with room air by means of induction.

Working document QAS/02.048/Rev.1 page 8

ULPA filter Ultra-Low Penetration Air filter. (not applicable to normal pharmaceutical installations, but given for background information) Validation The documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected results. Validation Master Plan (VMP) VMP is a high level document which establishes an umbrella validation plan for the entire project, and is used as guidance to the project team for resource and technical planning (also referred to as master qualification plan).

3.

SCOPE OF DOCUMENT

3.1

The guideline focuses primarily on the design and GMP requirements for HVAC systems for solid dosage facilities. It does not cover requirements for manufacturing sites for the production of sterile products, however, reference is sometimes made to sterile facilities for background or comparative purposes. There is very little definitive text relating to the HVAC or ECS systems for these facilities. However, most of the system design principles for Solid Dosage manufacturing facilities will also apply other facilities such as liquids, creams and ointments. This guideline is intended as a basic guide for use by GMP inspectors. It is not very prescriptive in specifying requirements and design parameters. There are many parameters affecting a cleanroom condition and it is, therefore, difficult to implicitly define the requirements for one particular parameter. Many manufacturers have their own engineering design and qualification standards. However, these requirements may vary from one manufacturer to the next. Design parameters should, therefore, be realistically set for each project, with a view to creating a cost-effective design, yet still complying with all regulatory standards and ensuring that product quality and safety are not compromised. The three primary aspects addressed in this manual are the roles that the HVAC system plays in product protection, personnel protection and environmental protection. These aspects are represented in the organigram below:

Working document QAS/02.048/Rev.1 page 9

GMP MANUFACTURING ENVIRONMENT

PRODUCT PROTECTION

PERSONNEL PROTECTION

ENVIRONMENT PROTECTION

Contamination (Product & Staff)

Prevent with dust

Protect from product

Prevent with

Avoid fume

cross-contamination

fumes

discharge

Correct temperature &

Acceptable comfort

Avoid effluent

humidity

Conditions

discharge

Avoid duct discharge

SYSTEMS

SYSTEM VALIDATION

Fig 3.1 The guide addresses the various system criteria as per the sequence set out in the organigram. 4.

PRODUCT PROTECTION

4.1

Contamination control Through all stages of processing, products should be protected from contamination and crosscontamination (refer to section 4.2 for cross-contamination control). These include contaminants resulting from inappropriate building finishes, plant layout, poor cleaning procedures, lack of staff discipline and a poor HVAC system.

Working document QAS/02.048/Rev.1 page 10

4.1.1

Cleanroom Concept Pharmaceutical manufacturing facilities where pharmaceutical products, utensils and manufacturing equipment are exposed to the environment, should be classified as “cleanrooms”. A cleanroom is an area or zone where the particulate and microbial contamination is limited to specified levels. Different standards relating to the classification of cleanrooms are referred to in the table under section 8.5.1. Normally the level of cleanliness should be defined by the number of contaminants per cubic metre of room air. The smaller the number of contaminants, the cleaner the room classification. Pharmaceutical manufacturing facilities should validate their systems to a defined cleanroom classification, on a risk based approach. Air supply filtration quality, as well as the air change rate, should ensure that the defined cleanroom classification is attained. Figure 4.1 below illustrates the ideal shell-like building layout to enhance containment and protection from external contaminants. The process core is regarded as the most stringently controlled Clean Zone which is protected by being surrounded by cleanrooms of a lower classification.

Fig. 4.1 Shell-like containment control concept In order to achieve a cleanroom environment the contaminants need to be removed. External contaminants should be removed by efficient filtration of the supply air.

Working document QAS/02.048/Rev.1 page 11

Internal contaminants should be removed by dilution and flushing of contaminants in the room, or by displacement airflow (refer to Figs 4.2 and 4.3 below for examples of airborne contaminant flushing methods).

Fig. 4.2. Turbulent dilution of dirty air

Working document QAS/02.048/Rev.1 page 12

Fig. 4.3 Unidirectional displacement of dirty air Explanatory note: To achieve a cleaner condition in a room, more air should be supplied to further dilute the contaminants. For each increase in cleanroom classification the air change rate should be increased accordingly. The ISPE Baseline Guide for Oral Solid Dosage Forms does not stipulate any minimum air change rate for non-sterile manufacturing facilities. The air change rates are to be determined by the designer, taking the various critical parameters into . Many multinational pharmaceutical manufacturers have their own minimum air change rate standards for oral dosage facilities, and these typically vary between 6 and 20 air changes per hour. The number of air changes per hour is one of the most important factors in determining an efficient air handling system. Primarily the air change rate should be set to a level that will achieve the required cleanroom classification. The room air change rate is also determined by the following considerations:  The quality and filtration of the supply air  Particulates generated by the manufacturing process  Particulates generated by the operators  Configuration of the room and air terminal locations  Sufficient air to achieve containment effect  Sufficient air to cope with the room heatload  Sufficient air to maintain the required room pressure

A further important concept in specifying cleanroom criteria should be that of the associated activity.

Working document QAS/02.048/Rev.1 page 13

Each cleanroom class should be specified as achieving the cleanroom classification under “asbuilt”, “at-rest” or “operational” conditions. (There is a significant difference in the air change rate requirements between “as-built”, “at-rest” and “operational” ratings and, therefore, this must be specified up front in the design criteria.)

Fig. 4.4 “As-built” condition

Working document QAS/02.048/Rev.1 page 14

Fig. 4.5 “At-rest” condition

Working document QAS/02.048/Rev.1 page 15

Fig. 4.6 „Operational‟ Condition

The “as-built” condition should relate to carrying out room classification tests on the bare room, without any equipment or personnel. The “at-rest” condition should relate to carrying out room classification tests with the normal production equipment in the room, but without any operators. Due to the amounts of dust usually generated in a solid dosage facility most cleanroom classifications are rated for the “atrest” condition. The “operational” condition should relate to carrying out room classification tests with the normal production process with equipment operating, and the normal staff present in the room. Generally a room that is tested for an “operational” condition, should be able to clean up to a higher “at-rest” cleanroom classification, after a short clean-up condition. The clean-up time should normally be in the order of 20 minutes. The relationship between “at-rest” and “operational” room classifications are often presented in GMP guides, as set out in the table below:

Working document QAS/02.048/Rev.1 page 16

Room Grade

A B C D

At-rest Condition Maximum number of particles permitted/m3 0,5 m 5 m 3 500 1 3 500 1 350 000 2 000 3 500 000 20 000

Operational condition Maximum number of particles permitted/m3 0,5 m 5 m 3 500 1 350 000 2 000 3 500 000 20 000 Not defined Not defined

The achievement of a particular cleanroom classification depends on a number of different criteria. All of the criteria should be addressed at the design stage. There should be a balance between the different criteria in order to create an efficient cleanroom. Some of the basic criteria to be considered should include:              4.1.2

Building finishes and structure Air filtration Air change rate or flushing rate Room pressure Location of air terminals and directional airflow Temperature Humidity Material flow Personnel flow Equipment movement. Process being carried out Outside air conditions Occupancy

Level of Protection Airborne particulates and degree of filtration should be considered a critical parameter with reference to the level of product protection required. There are three levels of protection, as defined in the ISPE OSD Baseline Guide, for manufacturing facilities, as listed below: Level 1 General: An area with normal housekeeping and maintenance e.g. Warehousing, Secondary Packing. Level 2 Protected: An area in which steps are taken to protect the exposed drug substance from contamination or degradation. e.g. Manufacturing, Primary Packing, Dispensing, etc. Level 3 Controlled: An area in which specific environmental conditions are defined, controlled and monitored to prevent contamination or degradation of the drug substance.

Working document QAS/02.048/Rev.1 page 17

The ISPE OSD Baseline Guide further states that there are no particulate classification requirements for OSD facilities, such as those that exist for aseptic processing. The level of protection and air cleanliness for different areas should be evaluated based on the product being manufactured, the process and the product’s susceptibility to degradation. The most commonly applied classification for open product zones in a solid dosage plant is a Grade D classification. This equates to a particulate level classification of ISO 14644-1 Class 8, “at-rest”, measured against particle sizes of 0,5 m and 5 m. Note that the ISO 14644-1 cleanroom standard for air classification has replaced the US Federal Standard 209 standard. Cleanroom standards, such as ISO 14644-1 provide the details of how to classify air cleanliness by means of particle concentrations. Whereas the GMP standards provide a grading for air cleanliness in of the condition (at-rest or operational), the permissible microbial concentrations, as well as other factors such as gowning requirements. GMPs and cleanroom standards need to be used in conjunction with each other in order to define and classify the different manufacturing environments.

4.1.3

Air filtration to control contamination The degree to which air is filtered plays an important role in the prevention of contamination and the control of cross-contamination. The type of filters required for different applications will depend on the quality of the ambient air and the return air (if applicable) and also on the air change rates. The same cleanliness level could be achieved with an high air change rate and low grade filters, or a low air change rate with high grade filters. The table below gives the recommended filtration levels for different Levels of Protection in a Pharmaceutical facility, bearing in mind that adjustments may need ti be made to suit local conditions. . Level of Protection Level 1 Level 2 & 3 Level 2 & 3

Recommended filtration Primary filters only – EN779 G4 filters Production facility operating on 100% outside air: Primary & Secondary filters – EN779 G4 and F8 filters Production facility operating on re-circulated plus ambient air: where potential for product cross-contamination exists. Primary, secondary & tertiary filters - EN779 G4, F8 and EN1822 H13 filters

The filter classifications referred to above relate to the EN1822 and EN779 test standards which are the latest filter test standards, recommended for international use. (EN 779 relates to filter classes G1 to F9 and EN 1822 relates to filter classes H10 to U16.)

Working document QAS/02.048/Rev.1 page 18

Referring to actual filter efficiencies can be very misleading as there are currently many different test methods, and each results in a different value for the same filter. Figure 4.7 below gives a rough comparison between the different filter standards. APPROXIMATION OF EQUIVALENT FILTER STANDARDS EU Class

14 13 12 11 10 9 8

%

(Average)

7 6

5 % (Average)

4 3

2

Eurovent Class – Eurovent 4/5 (2-9) Eurovent 4/9 (2-9) Eurovent 4/4 (10-14)

%

EN 779 & EN 1822

99,99995 99,9995 99,995 99,95

U16 U15 U14 H13

99,5 95 85 75

H12 H11 F9/H10 F8 F7

(Integral Value)

95 90 85 80 75 70 65

Arrestance %

95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20

F6

F5

G4 G3

G2 G1

Dust Spot Efficiency ASHRAE 52/76 BS6540 Part 1 (1985)

MPPS, DEHS Aerosol EN1822

CEN/TC/195 WG1-G1-F9 WG2-H10-16

Fig. 4.7 Comparison of filter test standards

Working document QAS/02.048/Rev.1 page 19

In selecting filters the manufacturer should have considered other factors, such as particularly contaminated ambient conditions, local regulations and specific product requirements. Good prefiltration is not a specific requirement, but it extends the life of the more expensive filters downstream. If failure of a HEPA filter would jeopardize the integrity of a product, a back-up HEPA filter in series should be considered. 4.1.4

Contamination by HVAC plant Materials for components of an HVAC system should be selected with care, as the materials from which these are manufactured can liberate particles into the supply air stream. Any components with the potential for liberating particulate or microbial contamination into the air stream should be located upstream of the final filters. Careful selection should be made of any materials downstream of the final filters to ensure that they cannot rust or oxidize, liberating particulate matter into the air stream. As far as possible for maintenance purposes, ventilation dampers, filters and other services should be designed and positioned so that they are accessible from outside the manufacturing areas. Facility design should be planned so that as many of the services as possible are accessible from service voids or service corridors.

4.1.5

Contamination by staff Staff or operators are a source of contamination and the facility design and operating procedures should be such as to minimise their contamination. . Directional airflow within production or packing areas should be an important means of contamination control. Airflows should be planned in conjunction with operator locations, so as to minimise operator contamination of the product and also to protect the operator from dust inhalation. Where the product could be harmful to the operator, an alternative arrangement should be made.

4.1.6

Airflow patterns Airflow patterns within a production room can effect the spreading of contaminants. HVAC air distribution components should be selected to prevent contaminants generated within the room from being spread. Supply air diffs of the high induction type should not be used in a cleanroom. High induction diffs, typically used for office type air conditioning, provide a high degree of air mixing by inducing room air into the supply air stream. Contaminants in the room are drawn vertically up to the ceiling via the induced air stream and mixed with the air being

Working document QAS/02.048/Rev.1 page 20

supplied into the room. This is a distinct disadvantage in a pharmaceutical manufacturing facility, as the contaminants liberated by operators, as well as process dust, are drawn into the supply air and disseminated throughout the room. Air diffs should be of the non-induction type, introducing air with the least amount of induction so as to maximize the flushing effect. Whenever possible, air should be exhausted from rooms at a low level, as this helps to flush contaminants from the area.

Working document QAS/02.048/Rev.1 page 21

Fig. 4.8 Induction diff (not recommended)

Working document QAS/02.048/Rev.1 page 22

Fig. 4.9 Perforated plate diff (recommended)

Working document QAS/02.048/Rev.1 page 23

Fig. 4.10 4.1.7

Swirl diff (recommended)

Unidirectional Airflow (UDAF) Protection Unidirectional flow air is sometimes used to provide product protection by supplying a clean air supply over the product, which minimizes the ingress of contaminants from surrounding area. (unidirectional airflow is the term that has replaced laminar airflow) Sampling cubicles, which are normally located in a warehouse, are areas of possible contamination of starting or raw materials. Containers brought from the warehouse (which is often a less clean environment) into the sampling cubicle for sampling, should be cleaned prior to entry to the sampling cubicle. Containers and materials should be protected from contamination when they are opened. Sampling should normally be carried out under a unidirectional airflow screen to ensure that clean air is flowing over the container when it is opened.. Where appropriate the unidirectional airflow should also provide protection to the operator from contamination by the product.

Working document QAS/02.048/Rev.1 page 24

Normally unidirectional flow provides a Class A (ISO Class 5, operational, 0.5 m) environment, but for a sampling cubicle this degree of protection is not required. Sampling should be carried out in the same environmental class that is required for the further processing of the product. A dispensary weigh booth should be provided with unidirectional airflow for product and operator protection, similar to that described for Sampling. The unidirectional flow can be either vertical flow or horizontal flow, and the flow pattern that provides the best protection for a particular application should be selected. Current GMP guides recommend that UDAF velocities, for Grade A conditions, should be 0.45 m/s, within a range of ±20%. However, when UDAF is applied to Sampling and Weighing a lower velocity can be selected, provided the required protection can be validated.

Fig. 4.11 Diagram indicating horizontal and vertical unidirectional flow 4.1.8

Infiltration Air infiltration, of unfiltered air, into a pharmaceutical plant should not be the source of contamination. Manufacturing facilities should be maintained at a positive pressure relative to the outside, to limit the ingress of contaminants.

Working document QAS/02.048/Rev.1 page 25

Where facilities are to be maintained at negative pressures relative to ambient, in order to prevent the escape of harmful products to the outside (such as penicillin and hormones), then special precautions should be taken. The location of the negative pressure facility should be carefully considered with reference to the areas surrounding it, and particular attention must be given to ensuring that the building structure is well sealed. Negative pressure zones should, as far as possible, be encapsulated by surrounding areas with clean air supplies, so that only clean air can infiltrate into the controlled zone. 4.2

Cross-contamination protection Through all stages of processing, products should be protected from cross-contamination. This can be achieved with the aid of the following methods.

4.2.1

Directional air movement One of the primary tools for cross-contamination control is correct directional air movement, which may be brought about by a pressure cascade system. In a multi-product OSD manufacturing area (e.g. tablet manufacturing site), the layout normally consists of a corridor with production cubicles located on either side of it. Different products are likely to be manufactured in each cubicle, and care should be taken that dust cannot move from one cubicle to another. Cross-contamination between products within a single room will not be addressed, as different products should never be processed in the same area at the same time. The pressure cascade should be such that air flows from the corridor into the cubicles, resulting in dust containment. The corridor should be maintained at a higher pressure than the cubicles, and the cubicles at a higher pressure than atmospheric pressure. (There are, however, some instances where cubicles or processes should be maintained at a negative pressure relative to atmosphere, in order to contain hazardous substances, such as penicillin or hormones, etc.) Containment can normally be achieved by one of various means such as:

4.2.1.1 Displacement concept (low pressure differential, high airflow) A low pressure differential can effectively separate clean and less clean adjacent zones, by means of a low turbulent “displacement” airflow. Typically a velocity of greater than 0,2 m/s should be attained, as if the velocity is too low, turbulence within the doorway could allow dust to escape. This displacement airflow should be calculated as the product of the door area and the velocity, which generally results in fairly large air quantities. With this concept, the air should be supplied to the corridor, flow through the doorway, and should be extracted from the back of the cubicle. Normally the cubicle door should be closed

Working document QAS/02.048/Rev.1 page 26

and the air should enter the cubicle through a door grille, although the concept can be applied to an opening without a door. The door containment airflow velocity could be considered a critical parameter, depending on a risk analysis. This method of containment is not the preferred method, as the measurement and monitoring of doorway velocities, is difficult. 4.2.1.2 Pressure differential concept (high pressure differential, low airflow) The high pressure differential between the clean and less clean zones should be generated by leakage through the gaps of the closed doors to the cubicle. The pressure differential concept should be carefully considered as to whether it is used alone or in combination with other containment control techniques and concepts, such as a double door airlock. The pressure differential should be of sufficient magnitude to ensure containment and prevention of flow reversal, but should not be too high so as to create turbulence problems. The most widely accepted pressure differential, to achieve containment, between the two adjacent zones is 15 Pa, but pressure differentials of between 5Pa and 20Pa could be acceptable. A control tolerance of ±3 Pa is achievable, and one then needs to analyse what the implications of the upper and lower tolerances would have on containment. Where the design pressure differential is too low, and tolerances are at opposite extremities, a flow reversal can take place. The effect of room pressure tolerances are illustrated in figure 4.12 below

Figure 4.12 Pressure Cascades

Working document QAS/02.048/Rev.1 page 27

In considering room pressure differentials, transient variations, such as machine extract systems, should be taken into consideration. Pressure control systems can be either active/automated or ive/manual. ive/manual control is preferable, as it tends to be more stable, is less costly and requires less maintenance. Manual control systems should be set up during commissioning, and should not change unless other system conditions change. Whichever pressure control device is used, the pressures should be validated, monitored and recorded on a regular basis, to compliance. The pressure differential between adjacent rooms could be considered a critical parameter, depending on a risk analysis. Airlocks should be an important component in setting up and maintaining pressure cascade systems. For critical installations such as sterile product manufacturing areas, airlocks should have interlocked doors, so that only one door can be opened at a time to ensure the pressure cascade is not compromised. In less critical situations, the doors may not need to be interlocked and the pressure cascade is reliant on staff discipline. There are three basic classifications of airlocks that are physically the same, but only the pressure cascade regime differs. The classifications are as follows and are demonstrated by figures 4.13 to 4.15:

Working document QAS/02.048/Rev.1 page 28

Fig. 4.13 Cascade airlock

Fig. 4.14 Sink airlock

Working document QAS/02.048/Rev.1 page 29

Fig. 4.15 Bubble airlock Cascade airlock - high pressure on one side of the airlock and low pressure on the other side. Sink airlock - low pressure inside the airlock and high pressure on both outer sides. Bubble airlock - high pressure inside the airlock and low pressure on both outer sides. Wherever possible, the door swing on airlocks should be such that the door opens to the highpressure side. All airlock doors should be provided with self-closers. Door closer springs, if used, should be designed to hold the door closed and prevent the pressure differential from pushing the door open.

Working document QAS/02.048/Rev.1 page 30

4.2.1.3 Physical barrier concept The use of an impervious barrier to prevent cross-contamination between two zones is the third segregation concept. (This would typically be the case where a barrier isolator, or pumped transfer of materials, is used.) These methods however, are often not practical in an OSD facility, where the transport of relatively large volumes of materials is involved. 4.2.1.4 Selecting the segregation concept The choice of which of the above three segregation concepts should be used should largely be dependent on the type of production process taking place. The displacement concept should ideally be used in production processes where large amounts of dust are generated. The pressure differential concept may normally be used in zones where there is little or no dust being generated. The choice of pressure cascade regime and choice of airflow direction should be considered in relation to the product being handled. Highly potent products should be manufactured under a pressure cascade regime that is negative to atmospheric pressure. The pressure cascade for each facility should be individually assessed according to the product handled and level of protection required. Building structure should be given special attention, because of the pressure cascade design. Airtight ceilings and walls, close fitting doors and sealed light fittings should be in place as these all have an impact on the HVAC system The designer should assess all of these items up front, and also advise the architect/developer of all the implications. 4.2.2

Unidirectional Airflow protection Unidirectional airflow (UDAF) protection is a further means of preventing cross-contamination between products. (See also text under clause 4.1.7) In order to achieve a Grade A condition, unidirectional airflow is required, together with the correct HEPA filtration, microbial control and a Grade B background.

4.2.3

Cross-contamination via HVAC supply air The two basic concepts of air delivery to pharmaceutical production facilities should be considered. The air handling system either supplies 100% outside air to the facility, or a limited amount of outside air is mixed with return air from the production rooms.

Working document QAS/02.048/Rev.1 page 31

Dust laden air, returned to the air handling unit for recirculation purposes, increases the possibility of cross-contamination in a multi-product plant. A re-circulation system may be acceptable, provided that suitable filtration is provided and there are no contaminants (such as fumes and volatiles) which cannot be removed by normal filtration. A risk analysis is required. A recirculation system should be provided with HEPA filters to ensure the removal of return air contaminants, so as to prevent cross-contamination. The HEPA filters for this application should have an EN1822 classification of H13. 4.2.4

Cross-contamination due to fan failure Failure of a supply air fan, return air fan, exhaust air fan or dust extract system fan, can cause a system imbalance, resulting in a pressure cascade malfunction with a resultant air flow reversal. Appropriate airflow alarm systems should be in place to sound an alarm if failure of a critical fan occurs. Central dust extraction systems should be interlocked with the appropriate air handling systems, to ensure that they operate simultaneously. Room pressure imbalance between adjacent cubicles which are linked by common dust extract ducting should be prevented, as cross-contamination can occur if the dust extract fan fails or is switched off. Air should not flow from the room with the higher pressure to the room with the lower pressure, via the dust extract ducting.

4.3

Temperature and humidity

4.3.1

General temperature and humidity requirements Temperature and humidity should be controlled where relevant, to ensure compliance with product manufacturing requirements, and to provide operator comfort where necessary (e.g. sterile product manufacture).

4.3.2

Product temperature requirements Temperature requirements for the various products being manufactured should be determined, and based on this the HVAC temperature control should be set The operating band or tolerance between the acceptable minimum and maximum temperatures should not be made too close

4.3.3

Product humidity requirements Product humidity requirements should be determined before commencing with the design. Hygroscopic products require special attention, including the HVAC system and building design.

Working document QAS/02.048/Rev.1 page 32

Cubicles, or suites, processing products requiring low humidities, should have well-sealed walls and ceilings and should also be separated from adjacent areas with higher humidities, by means of suitable airlocks. Precautions should be taken to prevent moisture migration that increases the load on the HVAC system. Humidity control should include removing moisture from the air, or adding moisture to the air, as relevant. Moisture removal, or dehumidification, may be achieved by means of either refrigerated dehumidifiers, or chemical dehumidifiers. Humidifiers should be avoided, if possible, as they tend to microbiological growth. However, humidifiers may occasionally be required to overcome static electricity problems, or to suit product demands. Moisture addition or humidification may be achieved by means of injecting steam into the air stream. A product contamination assessment is required to determine whether pure or clean steam is required for humidification purposes. Chemical additives in the boiler make-up water should be specified, to determine if this will have any detrimental effects on the product when steam humidifiers are used. Humidification systems should be well drained to ensure that no condensate collects in air handling systems. Other humidification appliances, such as evaporative systems, atomizers and water mist sprays, should not be used, due to the possible microbial contamination risk When specifying relative humidities, the associated temperature should also be specified. Generally, suites requiring conditions lower than 45% RH at a temperature of 22°C may require chemical driers to achieve the conditions. A low temperature chilled water/glycol mixture or refrigerant may be used as a cooling medium for dehumidification. Chemical driers or dehumidifiers employing a desiccant, such as silica gel or lithium chloride, to remove the moisture from the air, should have desiccant wheels of the non-shedding type and should not microbial growth. Where high humidity is required, care should be taken with the insulation of cold surfaces in order to prevent condensation within the cleanroom or on air-handling components. Controlling humidity by means of sensing and calculating the absolute humidity should be preferred to controlling relative humidity, as the absolute humidity control tends to be more stable. Relative humidity fluctuates with temperature variations, and this may result in control system “hunting”.

Working document QAS/02.048/Rev.1 page 33

4.3.4

Microbial growth High temperatures and high humidities may lead to accelerated microbial growth as microbes proliferate more readily under these conditions. High temperatures and high humidities cause excessive perspiration from operators. This increases risk of microbial contamination. At least where there are no specific product-related temperature or humidity requirements, and operator comfort is not considered important, the microbial risk should be assessed.

5.

PERSONNEL PROTECTION

5.1

Protection from dust Operators’ health should not be put at risk by being exposed to harmful products. Where possible, dust should be controlled at source and thus prevented from being released into the room. Pharmaceutical product dust and vapour can be harmful to operators, and liberation of these should be controlled and should be drawn away from the operator. Airflow should be carefully planned, to ensure that the operator does not contaminate the product, and so that the operator is not put at risk by the product.

5.2

Dust classification Dust-related hazards that operators may be subjected to should be assessed. An analysis of the type of dust, and toxicity thereof, is required and the airflow determined accordingly. Dust can be roughly classified by size according to the following:    

Coarse dust with size range of 50 to 500 µm (which settles rapidly) Fine dust with size range of 1,0 to 50 µm (which settles slowly) Ultra Fine dust with size range of <0,5 to 1,0 µm (which remains constantly suspended) Particles < 0,05 µm are considered to be vapours and not dust

Only dust particles that are greater than 10 µm are visible to the naked eye with good lighting and good eyesight. Therefore there could be a lot of dust in the air that cannot be seen, but is nevertheless a potential hazard. 5.3

Unidirectional Airflow protection Unidirectional airflow protection, either vertical flow or horizontal flow, is an efficient means of protection for both the operator and the product. The source of the dust and the position in which the operator normally stands should be determined before deciding on the direction of unidirectional flow. In Figure 5.1 below, the dust generated at the weighing station is immediately extracted via the perforated work-top, thus protecting the operator from dust inhalation, but at the same time

Working document QAS/02.048/Rev.1 page 34

protecting the product from contamination from the operator by means of the vertical unidirectional airflow stream.

Figure 5.1 Operator protection at weighing station In an application such as a dispensary weigh booth the unidirectional flow velocity should be considered with regard to the possible disruption of sensitive scale readings. In a weigh booth situation the aim should be to provide dust containment. Where necessary, the velocity may be reduced to prevent scale inaccuracies, provided that sufficient airflow is maintained to provide containment. An alternative to vertical unidirectional flow protection may be the use of horizontal unidirectional flow. Careful consideration should be given to the position in which the operator stands relative to the source of dust liberation.

Working document QAS/02.048/Rev.1 page 35

Figure 5.2 Operator protection by horizontal air flow

It should be ensured that the operator is not in the path of an airflow that could lead to contamination of the product.

Working document QAS/02.048/Rev.1 page 36

Once the system has been designed and validated with a specific operator and process layout, strict discipline should be maintained to ensure that the SOP is adhered to. Obstructions in the path of a unidirectional flow air stream may cause even more dust exposure to the operator. Fig 5.3 indicates the incorrect use of a scale, which has a solid back. The back of the scale should not block the return air path, causing air to rise up vertically, resulting in a hazardous situation for the operator.

Figure 5.3 Operator subject to powder inhalation due to obstruction

Working document QAS/02.048/Rev.1 page 37

Figure 5.4 indicates a situation where an open bin is placed below a vertical uni-directional flow distributor. The downward airflow should be prevented from entering the bin, and then being forced to rise up again, carrying dust up towards the operator’s face.

Figure 5.4 Operator subject to powder contamination due to air flow reversal in bin. Figure 5.5 shows that sometimes a solid worktop can cause deflection of the vertical unidirectional airflow resulting in a flow reversal. A possible alternative solution would be to have a 100mm gap at the back of the table, with the air being extracted here.

Working document QAS/02.048/Rev.1 page 38

Figure 5.5 Operator subject to powder inhalation due to worktop obstruction 5.4

Point extraction Wherever possible, the dust or vapour contamination should be removed at source. Point extraction, as close as possible to the point where dust is generated, should be employed. Point extraction should be either in the form of a fixed high velocity extraction point or an articulated arm with movable hood or a fixed extract hood. Dust extraction ducting should be designed to have sufficient transfer velocity to ensure that dust is carried away, and does not settle in the ducting. The required transfer velocity is dependent on the density of the dust; the denser the dust, the higher the transfer velocity should be. Transfer velocities for pharmaceutical dust, should generally be in the range of 18 to 20 m/s. Ventilation hand books can provide more detailed information on the required transfer velocities.

5.5

Directional airflow Point extraction alone is usually not sufficient to capture all of the contaminants, and general directional airflow should be used to assist in removing dust and vapours from the room. Typically in a room operating with turbulent airflow the air should be introduced from ceiling diffs and is extracted from the room at low level. The low level extract should assist in drawing air down and away from the operator’s face. The location of the extract grilles should be positioned strategically to draw air away from the operator, but at the same time prevent the operator from contaminating the product.

Working document QAS/02.048/Rev.1 page 39

When dealing with the extraction of vapours, the density of the vapour should be taken into . If the vapour is lighter than air, then the extract grilles should be at high level, or possibly at high and low level.

5.6

Air Showers When operators have been working in a dusty environment, their protective garments could become coated with a film of dust. Operators should change out of their protective garments before going to the canteen. Operators could through an air shower, prior to entering the change room, on leaving the production area. Air showers should be designed as an air lock, with high velocity air nozzles which blast air from the sides of the airlock, to dislodge the dust. Air extract grilles at low level should draw the air away and return it to the filtration system. Some air showers may also incorporate a vertical laminar section at the exit end, to additionally flush contaminants away.

Fig. 5.6 Air shower

5.7

Protective enclosures When dealing with particularly harmful products, additional steps, such as handling the products in glove boxes or using barrier isolator technology, should be used. For products such as hormones or highly potent , operators should wear totally enclosed garments, as indicated in Figure 5.7.

Working document QAS/02.048/Rev.1 page 40

In this instance a breathing air system should provide a supply of filtered and conditioned air to the operator. The air supply to this type of breathing apparatus should normally be through an air compressor. Filtration, temperature and humidity need to be controlled to ensure operator safety and comfort. 5.8

Operator comfort Maximum and minimum room temperatures and humidities should be appropriate. Temperature conditions should be adjusted to suit the protective clothing that the operators are wearing. Typical comfort condition of 18°C should be applicable in a sterile manufacturing area where full protective clothing is worn, whereas 21° to 22°C should be comfortable in an OSD facility where the dress code is less onerous.

Fig. 5.7 Protective garments

Recommended humidity comfort levels of 20%RH to 60%RH should be maintained where required. Fresh air rates supplied to the facility should comply with local regulations, to provide operator comfort and safety and also to provide odour or fume removal. Fresh air rate should also be determined by the leakage from the building, for pressure control purposes.

Working document QAS/02.048/Rev.1 page 41

6.

PROTECTION OF THE ENVIRONMENT

6.1

Exhaust air dust Exhaust air discharge points on pharmaceutical facilities, such as from fluid bed driers and tablet coating equipment, and exhaust air from dust extraction systems, carry heavy dust loads and should be provided with adequate filtration to prevent ambient contamination. On typical solid dosage plants, where the powders are not highly potent, final filters on a dust exhaust system should be fine dust filters having a filter classification of F9 according to EN779 filter standards. On systems where harmful substances such as penicillin, hormones, toxic powders and enzymes are exhausted, the final filters should be HEPA filters with an H12 classification according to EN1822 filter standards. For exhaust systems where the discharge contaminant is considered particularly hazardous, it may be necessary to install two banks of HEPA filters in series, to provide additional protection should the first filter fail. When handling hazardous compounds, safe change filter housings, also called “bag-in-bag-out” filters, should be used. All filter banks should be provided with pressure differential indication gauges, to indicate the filter dust loading. Monitoring of filters should be done at regular intervals, to prevent excessive filter loading that could force dust particles through the filter media, or could cause the filters to burst, resulting in ambient contamination. Filter pressure gauges should be marked with the clean filter resistance, and the change-out filter resistance. More sophisticated computer-based data monitoring systems may be installed, with preventive maintenance plans by trend logging. (This type of system is commonly referred to as a building management system (BMS), building automation system (BAS) or system control and data acquisition (SCADA) system.) An automated monitoring system should be capable of indicating any out-of-specification condition without delay, by means of an alarm or similar system. Reverse pulse dust collectors can be used for removing dust from dust extract systems. These units are usually equipped with cartridge filters that have a compressed air lance inside the filters. This pulses on a regular basis to blow the dust off the filter cartridges. Reverse pulse dust collectors should be able to operate continuously without interrupting the airflow. Alternative types of dust collectors, e.g. those operating with a mechanical shaker, require the fan to be switched off when the mechanical shaker is activated, in order to shake the dust off the filters. This disruption of airflow could occur during a production run, and the loss of airflow could disrupt the pressure cascade. This may result in cross-contamination. The mechanical shaker dust collectors should not be used for applications where continuous airflow is a requirement.

Working document QAS/02.048/Rev.1 page 42

A wet scrubber can be used, which usually operates on the principal of ing the dust-laden air through a water spray. Dust forms a slurry which is then usually ed to a drainage system. With all the above types of dust collectors and wet scrubbers, the exhaust air quality should be determined to see whether the filtration efficiency is adequate. Additional filtration may be required downstream of the dust collector. Air showers may be used to remove contaminants from garments before leaving the production facility. 6.2

Fume removal Although fume, dust and effluent control relating to the ambient are not GMP issues, but rather environmental issues, they could also become a GMP issue. For example if an exhaust air discharge point was close to the HVAC system fresh air inlet. Removal of fumes should be by means of wet scrubbers or dry chemical scrubbers (deep bed scrubbers). Wet scrubbers for fume removal should normally have various chemicals added to the water to increase the adsorption efficiency. Deep bed scrubbers should be designed with activated carbon filters, or chemical adsorption granular media. The chemical media for deep bed scrubbers should be specific to the effluent being treated. The type and quantity of the vapours to be treated should be known, to select the type of filter media as well as the volume of media required.

6.3

Effluent discharge Effluent control should be designed to ensure that systems like wet scrubbers, which could discharge contaminants into the drainage system, do not become sources of possible risk or contamination.

7.

SYSTEMS AND COMPONENTS

7.1

Air distribution Introduction Figure 7.1 below indicates a schematic diagram of an air handling system serving rooms with horizontal unidirectional flow, vertical unidirectional flow and turbulent flow respectively for rooms A, B and C.

Working document QAS/02.048/Rev.1 page 43

Normally, systems having a Class A or B and possibly C should have final filters terminally located.

Fig. 7.1 Horizontal unidirectional flow, Vertical unidirectional flow and Turbulent flow

The following air flow diagram (Fig. 7.2) would typically be for a system with lower cleanroom classification such as Class D. HEPA filters may be located in the air handling unit and not terminally. There may be alternative locations for return air, e.g. room D (low-level return air) and room E (ceiling return air). A cleanroom should be designed with low-level return. Where ceiling return air grilles are used a higher air change rate may be required to achieve a specified cleanroom classification. Low level return or exhaust air grilles are always preferred, however, this may not be possible in all instances, where some ceiling return will be needed.

Working document QAS/02.048/Rev.1 page 44

Fig. 7.2 Air handling system with HEPA filters in AHU. 7.2

Air handling unit configurations There are various air handling unit (AHU) configurations that may be used on a system. These are discussed below.

7.2.1

Recirculation system. The airflow schematics of the two previous systems (Figures 7.1 and 7.2) indicate airhandling units with return air, or recirculated air, having a percentage of fresh air make-up. Depending on the airborne contaminants in the return air system, it may usually be acceptable to use recirculated air, provided that HEPA filters are installed in the supply air stream to remove contaminants, and thus prevent cross-contamination. Recirculated air should not be used if there are no HEPA filters installed in the system, unless the air handling system is serving a single product facility and there is evidence that there is no possibility of cross-contamination. Recirculation of air from areas where pharmaceutical dust is not generated, such as secondary packing, will not require HEPA filters in the system.

Working document QAS/02.048/Rev.1 page 45

7.2.2

Full fresh air systems Figure 7.3 below indicates a system operating on 100% fresh air and would typically apply to toxic products where recirculation of air with contaminants is not advised. In locations with temperate climatic condition, differences between a system operating on 100% fresh air versus a system utilizing recirculated air with HEPA filtration should be considered. The required degree of air cleanliness in most OSD manufacturing facilities can normally be achieved without the use of HEPA filters. The degree of filtration on the exhaust air should be determined dependant on the exhaust air contaminants and local environmental regulations.

Fig. 7.3 Full fresh air system A 100% fresh air system, which employs an energy reclaim feature (shown in Figure 7.4 below), normally employs an energy recovery wheel which transfers heat between the inlet air and the exhaust air. The potential for air leakage between the supply air and exhaust air as it es through the wheel should be prevented. The relative pressures between supply and exhaust air systems should be such that the exhaust air system operates at a lower pressure than the supply system. A risk analysis for potential cross-contamination through an energy wheel should be carried out. Alternatives to the energy recovery wheel, such as crossover plate heat exchangers and water coil heat exchangers, may be used.

Working document QAS/02.048/Rev.1 page 46

Fig. 7.4 Full fresh air system with energy recovery 7.2.3

Additional System Components

An airflow schematic diagram for a typical system serving a low humidity suite, is represented in Figure 7.5. There are various means of drying air. The most common is the use of a chemical drier, which uses a rotating desiccant wheel, and which is continuously regenerated by means of ing hot air through one segment of the wheel. The figure indicates the chemical drier handling part of the fresh air/return air mixture on a by flow. The chemical drier can be positioned in various positions as follows:     

Full flow of fresh/return air Partial handling of fresh/return air (by- airflow) Return air only Fresh air only Precooled air with any of the above alternatives

The location of the chemical drier, and the decision as to whether precooling is required, should be considered in the design phase. Additional components that may be required on a system often depend on the climatic conditions and locations. These are items such as:     

Frost coils on fresh air inlets in very cold climates to preheat the air Snow eliminators to prevent snow entering air inlets and blocking air flow. Dust eliminators on air inlets in arid and dusty locations Moisture eliminators in humid areas with high rainfall Fresh air precooling coils for very hot climates

Working document QAS/02.048/Rev.1 page 47

8.

COMMISSIONING, VALIDATION AND MAINTENANCE

8.1

Commissioning Commissioning should involve the setting up, balancing, adjustment and testing of the entire HVAC system, to ensure that the system meets all the requirements, as specified in the Requirement Specification, and capacities as specified by the designer or developer.

Fig. 7.5 Air handling system with chemical drying The installation records of the system should provide documented evidence of all measured capacities of the system. These data should include items such as the design and measured figures for airflows, water flows, system pressures and electrical amperages. All these should be contained in the Operating and maintenance manuals (O & M manuals). Acceptable tolerances are for all system parameters should be specified prior to commencing with the physical installation After installation training should be provided in the operation of the system. This training should include aspects of the O & M manuals. O & M manuals, together with their as-built record drawings, should be maintained as reference documents for any future upgrades or plant alterations. Commissioning should be a precursor to system qualification and validation.

Working document QAS/02.048/Rev.1 page 48

8.2

Validation and qualification Validation and qualification are essentially the same concept. Validation is the documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected results. Qualification is the act of planning, carrying out and recording of tests on equipment and systems, which form part of the validation process, in order to demonstrate that it will perform as intended. Validation, therefore, refers to the overall concept of validation, including process validation, while qualification refers to the validation part of equipment and systems. In this sense, qualification is a part of validation. Validation is a many-faceted activity, and is beyond the scope of this manual. However, the basic concepts of validation in relation to the HVAC are set out below. The organigram below illustrates the relationship between Qualification and validation, e.g. a number of components or items of equipment could make up a system, and a number of systems could collectively form a process.

Fig. 8.1 Qualification is a part of validation Equip 1

Equip 2

Equip 3

Equip 4

System 1

Equip 5

Equip 6

Equip 7

System 2

Process

As an example, an air handling unit and HEPA filters forming parts of a system would be qualified; the end product, the quality of the air, would be validated. Systems and equipment are qualified, whereas processes are validated.

Working document QAS/02.048/Rev.1 page 49

8.2.1

Validation master plan (VMP) The validation master plan (VMP) is a document that summarizes the manufacturer’s overall philosophy and approach, to be used for establishing performance adequacy. The VMP for a particular project, such as the HVAC, should describe the “What, Why, When, How, Where and Who” of the validation process. It should define the nature and extents of testing expected, and outline the test procedures and protocols to be followed, to accomplish validation. Stages of the qualification of the HVAC system should include DQ, IQ, OQ, and PQ. 

Design qualification (DQ) Design qualification is the documented check of planning documents and technical specifications, for design conformity with the URS, cGMP and regulatory requirements.



Installation qualification (IQ) Installation qualification is the documentary evidence to that the premises, HVAC system, ing utilities and equipment have been built and installed in compliance with their design specification.



Operational qualification (OQ) Operational qualification is the documented verification that all aspects of a facility, utility or equipment that can effect product quality, operate as intended through all anticipated ranges.



Performance qualification (PQ) Performance qualification is the documentary evidence to that the plant, system or equipment operates consistently and reproducibly within the defined specifications and parameters, for a prolonged period.

8.3

What to qualify For all HVAC installation components, sub-systems or parameters, critical parameters and noncritical parameters should be determined, by means of a risk analysis. If the component comes into direct with the product, or if the parameter affects the quality of the drug product, then it should be classified as a critical parameter. Critical parameters should be qualified. A realistic approach to differentiating between critical and non-critical parameters is required, in order not to make the validation process unnecessarily complex. 

The room humidity, where the product is exposed, should be considered a critical parameter when a humidity-sensitive product is being manufactured. The humidity sensors and the humidity monitoring system, should, therefore, be qualified. The heat

Working document QAS/02.048/Rev.1 page 50

transfer system, chemical drier or steam humidifier, which is producing the humidity controlled air, is further down the line and may not require operational qualification. 

A room cleanliness classification is a critical parameter and, therefore, the room air change rates and HEPA filters should be critical parameters and require qualification. Items such as the fan generating the airflow and the primary and secondary filters are non-critical parameters, and may not require operational qualification.

In the above examples reference is made to non-critical components that may not require operational (and performance) qualification. However, these components, and in fact the entire HVAC system, should be subject to design qualification (DQ) and installation qualification (IQ). Systems and components, which are non-critical components, should be subject to Good Engineering Practice (GEP) reviews in lieu of OQ and PQ. GEP assures that the facility has been built in accordance with plans and specifications and that construction, installation, commissioning and testing have been performed properly. Strict change control procedures should be applied to any items that affect critical parameters, such as the HVAC system or component, control system settings and SOPs that affect critical parameters. 8.4

Setting qualification limits The validation master plan (VMP) should be prepared before the system design commences, as the requirements set out in the VMP will influence the design. Acceptance criteria and limits cannot be imposed once the system has already been designed and installed. The relationships between design conditions, operating range and validated acceptance criteria, are given in Fig. 8.2 below.

Working document QAS/02.048/Rev.1 page 51

Fig. 8.2 System operating ranges Design condition relates to the specified range or accuracy of a controlled variable used by the designer as a basis to determine the performance requirements of an engineered system. The design range should be within the normal operating range. Normal operating range is the range that the manufacturer selects as the acceptable values for a parameter during normal operations. This range should be within the operating range. Operating range is the range of validated critical parameters within which acceptable products can be manufactured. Alert limit indicates that the normal operating range of a critical parameter has been exceeded and that corrective measures may need to be taken, to prevent the action limit being reached. (in some cases data review only may be required) Action limit indicates that the validated acceptance criteria of a critical parameter have been exceeded and that appropriate countermeasures are required. During system operational qualification all parameters should fall within the design condition range. However, during normal operating procedures it is acceptable for the conditions to go out of the design condition range, but should remain within the operating range. For example, a moisture-sensitive product could require a room design condition of 35%RH ± 5%RH, but the normal operating range could be 35%RH ± 10%RH. The operating range may be set at 35%RH ± 15%RH and if the room condition goes above 50%RH (35% + 15%) or below 20%RH (35% - 15%), then the action limits have been exceeded.

Working document QAS/02.048/Rev.1 page 52

Action limit deviations should form part of the batch records as they represent a deviation from the validated parameters. The relationship between temperature and humidity should be specified when setting limits for room temperatures and humidities. A very tight humidity tolerance, but a wide temperature tolerance, should not be acceptable, as variances between the maximum and minimum temperature condition will give an automatic deviation of the humidity condition. Design condition and normal operating ranges should be set as wide as possible to set realistically achievable parameters. 8.5

Parameters to qualify For a pharmaceutical facility some of the typical HVAC system parameters that should be qualified include:             

room temperature (if there is an impact on product quality) room humidity (if there is an impact on product quality) supply air quantities for all diffs return air or exhaust air quantities room air change rates room pressures room air flow patterns laminar flow velocities containment system velocities HEPA filter penetration tests room particle counts room clean-up rates microbiological air and surface counts

Return air and exhaust air quantities are sometimes in conflict with room pressures. At the design stage it is not always possible to determine exact leakage from building components as this is often outside of the control of the designer. For example, the leakage through doors is dependent upon the fit of the doors. Room return or exhaust air is a variable which is used to set up the room pressure. As room pressure is a more important criteria than the return air, the latter should have a very wide Normal Operating Range. The maximum time interval of the 24 months between tests, as given in the table of ISO 14644 Optional Strategic Tests, should be considered in conjunction with the type of facility under test and the product Level of Protection. Retesting should also be done when any change takes place, which could affect system performance. Requalification of these parameters should be done at regular intervals, e.g. at least annually. The tables below, giving the recommended time periods for retesting or requalification, are taken from the ISO 14644 standard and are given for reference purposes only. The actual test periods may be more frequent or less frequent, depending on the product and process.

Working document QAS/02.048/Rev.1 page 53

STRATEGIC TESTS (ISO 14644) Schedule of Tests to Demonstrate Continuing Compliance Test Parameter Cleanroom Max Time Class Interval All classes 6 Months Particle Count Test (Verification of Cleanliness)

Air Pressure Difference (To non crosscontamination)

All classes

12 Months

Airflow Volume (To air change rates)

All Classes

12 Months

Airflow Velocity (To unidirectional flow or containment conditions)

All Classes

12 Months

Fig. 8.3

Test Procedure Dust particle counts to be carried out & result printouts produced. No. of readings and positions of tests to be in accordance with ISO 14644-1 Annex B Log of pressure differential readings to be produced or critical plants should be logged daily, preferably continuously. A 15 Pa pressure differential between different zones is recommended. In accordance with ISO 14644-3 Annex B5* Air flow readings for supply air and return air grilles to be measured and air change rates to be calculated. In accordance with ISO 14644-3 Annex B13* Air velocities for containment systems and unidirectional flow protection systems to be measured. In accordance with ISO 14644-3 Annex B4*

Working document QAS/02.048/Rev.1 page 54

RECOMMENDED OPTIONAL STRATEGIC TESTS (ISO 14644) Schedule of Tests to Demonstrate Continuing Compliance Test Parameter Cleanroom Max Time Class Interval All Classes 24 Months Filter leakage Tests (To filter integrity)

Containment leakage (To non crosscontamination)

All Classes

24 Months

Recovery (To clean up time)

All Classes

24 Months

Airflow Visualization (To required air flow patterns)

All Classes

24 Months

Fig. 8.4

Test Procedure Filter penetration tests to be carried out by competent person to demonstrate filter media and filter seal integrity. Only required on HEPA filters. In accordance with ISO 14644-3 Annex B6* Demonstrate that contaminant is maintained within a room by means of:  airflow direction smoke tests  Room air pressures. In accordance with ISO 14644-3 Annex B4* Test to establish time that a clean room takes to recover from a contaminated condition to the specified clean room condition. Should not take more than 15 min. In accordance with ISO 14644-3 Annex B13* Tests to demonstrate air flows:  from clean to dirty areas  do not cause crosscontamination  uniformly from unidirectional flow units Demonstrated by actual or videoed smoke tests. In accordance with ISO 14644-3 Annex B7*

Working document QAS/02.048/Rev.1 page 55

The table below sets out the permissible particle concentrations for various cleanroom classifications, as well as a comparison between different cleanroom standards. The ISO 14644 standard has superseded the US and BS standards, but these are given for comparative purposes only. ISO Classes 1 to 4 are not applicable to pharmaceutical facilities, but these Classes are included for completeness of the table.

8.5.1 CONTROLLED ENVIRONMENT STANDARDS BS EN ISO 1 4644-1: 1999, Federal Standard and Approximate Equivalents

ISO Classification Number (N)

Maximum concentration limits (particles/m³ of air) for particles equal to and larger than the considered sizes shown below.

0.1µm

0.2 µm

ISO Class 1

10

2

ISO Class 2

100

24

0.3 µm

10

0.5 µm

1µm

5µm

Approx. Equivalent American Federal Standard 209E 209D

BS5295 1989

EEC (GMP)

4 M1

ISO Class 3

1 000

237

102

35

8

M1.5

1

(C)

10

(D)

M2 ISO Class 4

10 000

2 370

1 020

352

83

M2.5 M3

ISO Class 5(U)

100 000

23 700

10 200

3 520

832

29

M3.5

100 (U)

E

A

ISO Class 5(N)

100 000

23 700

10 200

3 520

832

29

M3.5

100 (N)

F

B

1 000

G or H

10 000

J

C

100 000

K

D

M4 ISO Class 6

1 000 000

237 000

102 000

35 200

8 320

293

M4.5 M5

ISO Class 7

352 000

83 200

2 930

M5.5 M6

ISO Class 8

3 520 000

832 000

29 300

M6.5 M7

ISO Class 9

35 200 000

U = unidirectional flow, N = non-unidirectional or turbulent flow

Fig. 8.5

8 320 000

293 000

L

Working document QAS/02.048/Rev.1 page 56

Clean-up times normally relate to the time it takes to “clean up” the room from one class lower to the specified class. For example the recommended time to clean up from a Class D (ISO 8) to a Class C (ISO 7) condition should be within 15 minutes. The relationship between cleanroom “at rest” and “operational” conditions may be used as the criteria for clean-up tests, i.e. the clean-up time can be expressed as the time to change from an “Operational” condition to an “at Rest” condition. This relationship is tabulated below. ISO 14644-1 Class

At rest In operation Maximum permitted number of particles/m3 equal to or above 0,5 m

5m

0,5m

5m

EC Grade A

3 500

30

3 500

30

(U)

ISO 5 equivalent

ISO 5 equivalent

ISO 5 equivalent

ISO 5 equivalent

EC Grade B

3 500

30

35 000

300

(N)

ISO 5 equivalent

ISO 5 equivalent

ISO 6 equivalent

ISO 6 equivalent

EC grade not

35 000

300

350 000

3 000

defined

ISO 6 equivalent

ISO 6 equivalent

ISO 7 equivalent

ISO 7 equivalent

EC Grade C

350 000

3 000

3 500 000

30 000

ISO 7 equivalent

ISO 7 equivalent

ISO 8 equivalent

ISO 8 equivalent

3 500 000

30 000

35 000 000

300 000

ISO 8 equivalent

ISO 8 equivalent

ISO 9 equivalent

ISO 6 equivalent

EC grade not

35 000 000

300 000

Not defined

Not defined

defined

ISO 9 equivalent

ISO 9 equivalent

EC Grade D

U = unidirectional flow & N. = non-unidirectional flow or turbulent flow

Fig. 8.6

The relationship between cleanroom particulate counts and cleanroom microbial counts as given by various standards are tabulated below. ISO 14644-1 Class

EC Grade A

Recommended limits for microbial contamination (average values) Air sample Settle plates plates Glove print cfu/m3 5 fingers (90mm) (55mm) cfu/glove cfu/4hours cfu/plate <1 <1 <1 <1

ISO 5 (U) EC Grade B

10

5

5

5

50

25

10

-

100

50

25

-

ISO 5 (N) EC not defined ISO 6 EC Grade C

Working document QAS/02.048/Rev.1 page 57

ISO 7 EC Grade D

200

100

50

-

Not defined

Not defined

Not defined

Not defined

ISO 8 EC not defined ISO 9

Fig. 8.7

Working document QAS/02.048/Rev.1 page 58

8.6

Maintenance The HVAC system should be subjected to planned preventative maintenance. Maintenance should be done in accordance with written procedures and records of maintenance should be kept. HVAC systems for cleanroom facilities are normally sophisticated and maintenance staff should be adequately trained. HEPA filters should only be changed by specialists or trained personnel. Maintenance of the HVAC system, with regards to component accessibility, should be considered during the design stage of the system. Where possible, items requiring routine maintenance should be located outside of the clean zones. Any maintenance activity should be critically assessed to determine any impact on product contamination. Maintenance activities should normally be scheduled to take place outside of production hours, and any system stoppage should be assessed with a view to possible re-qualification of an area that may be required as a result of an interruption of the service. Prevention of operator contamination should also be addressed at the design stage, e.g. exhaust air filters that could be contaminated with harmful products may require safe-change filter housings.

Working document QAS/02.048/Rev.1 page 59

8.7

Inspections

The table below lists some of the HVAC related items that the inspector could check on a typical pharmaceutical facility. Facility Inspection List

Date inspected:

Facility name:

Inspected by:

Area

Item to inspect

Warehouses & Storage facilities

Temperature monitoring High and Low level records required Compliance with temperature and humidity parameters Warehouse should preferably be at a positive pressure to ambient Raw materials testing method Contamination Protection Booth positive pressure Adequate filtration

Materials Sampling areas

Adequate dust removal Dispensary areas

Pressure cascade system Product protection Operator protection Compliance with temperature and humidity parameters Compliance with cleanroom class specification Records of filter penetration tests

Production Corridors

Corridor over pressure monitoring Compliance with temperature and humidity parameters Compliance with cleanroom class specification Air flow pattern documentation

Liquids Manufacture

Prevention of cross contamination (what measures have been taken) Room pressure monitoring Compliance with temperature and humidity parameters Compliance with clean room class specification Air flow pattern documentation Filter penetration test records

Comments

Working document QAS/02.048/Rev.1 page 60

Facility Inspection List

Date inspected:

Facility name:

Inspected by:

Area

Item to inspect

Granulation and

Compliance with temperature and humidity parameters Compliance with clean room class specification Air flow pattern documentation Removal of excess dust by means of dust extraction systems Operator protection Room pressure records Adequate filtration on fluid bed driers and ovens

Blending areas

Compression and Encapsulation

Room pressure monitoring Compliance with temperature and humidity parameters Compliance with clean room class specification Air flow pattern documentation

Coating

Check room ratings for use of items such as solvents Filtration on hot air blowers Room pressure monitoring Cleanroom classification Compliance with temperature and humidity

Packing Areas

Room pressure monitoring Compliance with temperature and humidity parameters Compliance with clean room class specification Air flow pattern documentation Primary and secondary packing segregated

Personnel access and Change rooms

Pressure cascaded system Sufficient air locks Compliance with cleanroom class specification – are they the same class as the area they serve?

Comments

Working document QAS/02.048/Rev.1 page 61

Facility Inspection List

Date inspected:

Facility name:

Inspected by:

Area

Item to inspect

General HVAC Items Ask for the following:

Temperature & humidity logging data for stability rooms Room pressure test results Room particle count test results Check that room particle count tests procedures were in accordance with applicable standards Airflow readings and room air change rate data General proof that the conditions are under control (OQ & PQ documentation) HEPA filter penetration test results Are supply and extract grilles in correct position. Is exhaust air adequately filtered Are fan failure safe shut-down procedures in place Room dust containment tests Check the process air filtration, is it sufficient? (on fluid bed driers, ovens, coating pans, etc.) Are HVAC system components in correct sequence?

Comments

Working document QAS/02.048/Rev.1 page 62

REFERENCES 1.

ASHRAE Handbook 2000 HVAC Systems and Equipment.

2.

ISPE Baseline Pharmaceutical Engineering Guides for New Facilities - Volume 2: Oral Solid Dosage Forms - First Edition / February 1998.

3.

ISPE Baseline Pharmaceutical Engineering Guides for New and Renovated Facilities – Volume 3: Sterile Manufacturing Facilities – First Edition/January 1999.

4.

ISPE Baseline Pharmaceutical Engineering Guides for New and Renovated Facilities – Volume 5: Commissioning and Qualification - First Edition / March 2001.

5.

International Cleanroom Standards - ISO 14644 Parts 1 to 6.

6.

Luwa “Introduction to High Efficiency Filtration”, bulletin 50.10.10 Sheet 020.

7.

Pharmaceutical Inspectorate Convention Pharmaceutical Inspection Co-operation Scheme – Guide to Good Manufacturing Practice for Medicinal Products: PH 1/97 (Rev. 3) 15 January 2002.

8.

PIC/S Pharmaceutical Inspection Convention/ Pharmaceutical Inspection Co-operation Scheme PH 1/97 (Rev.3) Guide To Good Manufacturing Practice for Medicinal Products.

9.

Pharmaceutical Manufacturers Association of South Africa - Guide to Good Pharmaceutical Manufacturing Practice.

10.

Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1 - World Health Organisation, Geneva (1997).

11.

Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 2 (Good Manufacturing Practices and Inspection) - World Health Organisation, Geneva (1999).

12.

The Rules Governing Medicinal Products in the European Community - Volume IV – Good Manufacturing Practice for Medicinal Products.

13.

Woods Practical Guide to Fan Engineering.

* * *