GMP for Utilities and Services Edited and revised by Dr. Harbant (April, 2012)

Topics Design for utilities and services Sizing of systems for Batch production Solid transfer cleaning systems Effluent treatment and Waste minimization General Engineering Practice requirements

Defining utilities and services Heating, Ventilation and Air-Conditioning (HVAC) play an important role in ensuring the manufacture of quality bio-based products. A well designed HVAC system will also result in operator comfort. Utilities is infrastructure setup for manufacturing bio products Manufacturing services is to use the structure

Utilities that follow GMP should 1.Appropriate in design -Building (the plan, size, shape, what is in the building, maintenance, plant access, storage of consumables) 2. Equipment history and records or database 3. Written procedures and evidence procedures are followed 4. A maintenance programme

Type of system categories that may be required and the areas of utilization and also the checklist for determining possible requirements for utility systems.

Site Preparation and Plant Design  Site arrangement and over-all layout design (green space parking, traffic, Recreation area, tanks, site utilities, etc..)  Water supply and waste management area (waste contractors)  Site security and access (fences, guard, cameras, etc..)  Utilities design, layout, backup (critical utilities backup)  Equipment-design, LAYOUT, spares, capacity. 6~kfk~

Continue….  Safety (Personnel and Equipment), emergency services access.  External architecture should take in account the local environment (temperature, humidity, wind, etc..)  Ease of maintenance (services ducts, cat floor, etc..)  Project management (Managers, consultants, etc..)  Validation Plans and an effective change control procedures. Provision of design and (as built) drawings.  CONTRACTOR (Experience contractor) 7~kfk~

Utilities Production Area Waste Treatment Complex Area Stores Administration Building 8~kfk~

Waste Treatment Complex Area Production Area II (Future Plan ) Production Area I Administration Building Utilities Stores 9~kfk~

Less Engineering work and ease for new facility building Less Cost if it the facility was designed from the beginning to have extra-capacity for the stores, utility and waste management system System Uniformity for utilities (Equipment in Piping) Higher assess value factory Points to consider in designing from the beginning for an extension plan that will give a factory the following advantages! 10~kfk~

Engineering and Design Lifecycle Pre-conceptual Design Conceptual Design Basic Design Detail Design 11~kfk~

 Layout Options (Single floor vs. Multi floor, Different options of facility design)  Room Classification (Area and Classes)  Commissioning and Qualification Approach  Equipment List  Time Schedule  Price Estimation Pre-conceptual Design 12~kfk~

 Layout  Room Classification  Material, product & Personnel flows  Process Automation system  Draft Equipment requirement specifications  Draft qualification Master Plan  Process/clean utilities/ flow diagrams  HVAC zoning  Detailed time schedule  Detailed price estimate Conceptual Design 13~kfk~

 Final Layout with complete building specification  Room Classification (Final)  Material, product & Personnel flows (Final)  Process Automation system (Final)  Equipment requirement specifications  Draft qualification Master Plan  Process/clean utilities/ flow diagrams  Complete HVAC Design  Qualification Master Plan  Estimate price of the project (± 30 %) Basic Design 14~kfk~

 Usually done by consultant engineering company  Complete 3D design of the facility including: Engineering, pipe work, HVAC ducting, Electrical Module and wiring  Complete specifications of all part of the project for  Building complete specifications  Equipment (size, capacity, utility requirements, net- working, etc..)  Final walk through model (material flow, personnel flow, etc..)  Possibly with complete operation model (Chem-CAD model) Detail Design 15~kfk~

Division of utility and service system design are: 1.HVAC 2.Air 3.Vacuum 4.Clean steam 5.Inert gases 6.Specialist water supplies 7.Heat transfer fluids 8.Refrigeration systems

Heating, Ventilation and Air-Conditioning (HVAC) HVAC system design influences architectural layouts with regard 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. Temperature, relative humidity and ventilation should be appropriate and should not adversely affect the quality of pharmaceutical products during storage.

Primary aspects of HPAC Many manufacturers have their own engineering design and qualification standards and 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 the HVAC system plays in product protection, personnel protection and environmental protection.

HPAC (Protection concept) Manufacturing areas where pharmaceutical starting materials and products, utensils and equipment are exposed to the environment, should be classified as “clean areas”. Some of the basic criteria to be considered should include: i. Building finishes and structure ii. Air filtration iii. Air change rate or flushing rate iv. Room pressure v. Location of air terminals and directional airflow vi. Temperature vii. Humidity viii. Material flow ix. Personnel flow x. Equipment movement xi. Process being carried out xii. Outside air conditions xiii. Occupancy

Protection from contamination Materials and products should be protected from contamination and cross- contamination through all stages of manufacture Contaminants should be removed through effective ventilation. External contaminants should be removed by effective filtration of the supply air using the Shell-like containment control concept in which internal contaminants are diluted and flushed off in the room, or by displacement airflow Examples of levels of protection include: 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 pharmaceutical starting material or product 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 pharmaceutical starting material or product.

Clean area classification Each clean area class should be specified as achieving the clean area classification under “as-built”, “at-rest” or “operational” conditions. 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 clean area classifications are rated for the “at-rest” condition. The “operational” condition should relate to carrying out room classification tests with the normal production process with equipment operating, and the normal number of personnel present in the room. Generally a room that is tested for an “operational” condition should be able to clean up to the “at-rest” clean area classification, after a short clean-up time.

Air change rates for clean area Air change rates normally vary between 6 and 20 air changes per hour and are normally 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 supply and extract locations Sufficient air to achieve containment effect Sufficient air to cope with the room heat load Sufficient air to maintain the required room pressure

Dust control 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 so as to have sufficient transfer velocity to ensure that dust is carried away, and does not settle in the ducting. The required transfer velocity should be determined as it is dependent on the density of the dust (the denser the dust, the higher the transfer velocity should be, e.g m/s). 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.

Contd. Dust-related hazards that operators may be subjected to should be assessed. An analysis of the type of dust and toxicity thereof should be done and the airflow determined accordingly. 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 diffusers and 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.

Protection of the environment Exhaust air dust Fume removal

2) Air a)Compressed air  Compressed air is used in pharmaceutical applications for driving pumps and back flushing bag filters.  Atmospheric air is passed through a 50 urn or smaller aperture filter to remove insects, dust and pollen before it enters the compressor.  The air is compressed to an appropriate pressure for the system, taking into account the maximum required design pressure and distribution system pressure drop.  The pipework is usually carbon steel or galvanized carbon steel.

 A general specification for air for these duties is: particulate filtration to 0.1 micron; pressure dew point at 7Barg H- 30C; oil filtration to 0.01 ppm; normal operating pressure 7Barg.

b) Instrument air  Instrument air is used for actuating valves  The specification of the air varies according to user requirements and guidance should be sought from valve suppliers.  A general specification for instrument air is: particulate filtration to 0.01 micron; pressure dew point at 7Barg — 400C; oil filtration to ppm; normal operating pressure 7Barg.

c) Breathing air  Breathing air is used to protect personnel from dust and toxic fumes by supplying air to hoods or full suits.  The breathing air system is usually supplied from the compressed air system.  The air is then filtered, purified and dried before distribution to the end users.  The use of compressed air for breathing means that the location of the compressor air inlet is especially important to prevent toxic fumes from entering the breathing air system.

3) Vacuum  General vacuum systems are normally connected to a number of process vessels through a common pipeline and used for evacuating process equipment prior to nitrogen blanketing, filling head tanks from drums and transferring from one vessel to another.  The actual vacuum achieved is not critical, but is of the order of 200mBarg.  For filtration, a vacuum pump is normally connected to a single filter via a receiver. The pipework is commonly stainless steel as a minimum, as the filtrate is often reused either directly or after distillation.

 For drying, the vacuum may be used to dry the solid on the filter by applying to the top of the filter or dryer.  The vacuum used for drying will depend upon the maximum temperature which can be applied to the product balanced against the likelihood of pulling solids into the vent filter causing a blockage.  The use of vacuum in distillation systems on pharmaceutical facilities is common, in order to depress the boiling point of distillation mixtures where some component of the mixture is sensitive to heat.

 There are two main types of vacuum pump: a)Liquid seal – Liquid seal pumps use fluid to provide a liquid seal between the pump casing and the central impellor. – The seal fluid can be run on a single pass or on recirculation. – A single pass type is the most appropriate choice for vapour streams containing solids, condensed solvent vapours or corrosive gases.

- Recirculating seal fluid systems require additional equipment such as a cooler (to remove heat from the condensing process vapours and the power of the pump motor) and a pot that can be topped up with fresh sealing fluid and which has an overflow to drain. -The recirculating system produces less effluent but if not correctly maintained or cleaned can become blocked with solids or the seal fluid can be completely displaced by solvent.

b) Dry running - Dry running pumps are similar in operation to liquid ring pumps but use oil for the lubricating fluid. - The tolerances within the pump are much smaller and, therefore, much less oil is required. - The choice of lubricating oil is important as this can react with the process vapours and choke the pump.

4) Clean steam  Clean steam is used in pharmaceutical applications where steam or its condensate is in direct contact with the product.  The requirement to use clean or pure steam is governed by the cGMP to avoid contamination of the product.  The major use for clean steam is in the sterilization of process and specialist water systems.  Clean steam is also used in autoclaves and sometimes for the humidification of clean rooms.  Pure steam is used in processes producing parenterals, which demand the use of WFI and here the steam must not be contaminated with micro-organisms or endotoxins (pyrogens).

 Clean steam and pure steam are usually produced in a dedicated steam generator.  Steam is a sterilizing agent so although the materials of construction are required to be 316 or 304 stainless steel for reasons of corrosion resistance, the pipelines do not require special internal finishes and can be connected using flanges.

 Nitrogen is used to blanket vessels, for liquid transfers, filtration, cleaning bag filters, and for blowing process lines clear.  It is also used for inerting explosive atmospheres in solids handling equipment and for pressure testing vessels.  Nitrogen can be produced in pressure swing absorption systems from air, by other means from air, or from liquefied nitrogen in storage tanks and cylinders. 5) Inert gases

 Liquid nitrogen can be produced in many different grades and, therefore, it is important to select the correct grade for the application.  It must be remembered that the grade must be for the highest requirement if the system is for site wide nitrogen supply.  The material of construction for pipework is usually carbon steel.  The highest pressure required and the maximum line pressure drops set the pressure of the main.

6) Specialist water supplies  This section offers an overview of the main aspects of water and steam production and use in pharmaceutical facilities.  There are many types of water to be found in pharmaceutical facilities.  A few of the main types are as follows: Towns water is usually straight from the mains and may vary in quality throughout the year. There may be two or more water sources for a given plant, and the characteristics of water from these different sources may vary widely. Process water is normally towns water that has passed through a site break tank;

de-ionized/demineralized and softened water has passed through some form of water softening process to remove calcium and magnesium ions that cancause scale on heat exchanger surfaces and in reactors; purified water has usually been softened and passed through a UV source to remove bacteria. water for injection/pyrogen-free water has been softened and has a low bacterial count and a reduced endotoxin loading. There are a number of different specifications for this type of water. The USP and BP specifications are the most commonly used for WFI.

7) Heat transfer fluids  Hot oil is used for reaction temperatures greater than about 180°C and is dedicated to a small number of reactors.  The system consists of an electrically heated element, pumped loop, distribution pipework and expansion tank. The type of oil specified is dependant upon the desired operating range, but the oils are normally silicone based and, therefore, have high boiling points and are highly stable at sustained high temperatures.

8) Refrigeration systems  'Fridge' systems are used to cool reactors, in batch crystallization or as vent condensers on volatile solvent tanks.  Glycol is usually used as the heat transfer medium with ethylene glycol being used for nonfood use and propylene glycol for food use.  The concentration of glycol is specified by the desired minimum operating temperature of the process vessels, so care must be taken to ensure that the glycol concentration remains at the required level.

Sizing of Systems for Batch Production

The sizing of utilities requires a good knowledge of all the operations in the plant including the other utility operations and HVAC requirements. Information required: – Mass balance – Energy balance – Batch times – Mode of operation

Electricity A motor list is usually made which details power requirements and whether the power requirement is intermittent or continuous. It is necessary to construct a switch room for housing the MMC panels and control equipments.

Cooling water The cooling requirement is possible to calculate with the used of mass balance and batch times. Cooling requirements: – HVAC and refrigeration requirements – Gantt Chart ( if the process has more than one stage running) – Future expansion requirements

Steam Additional consideration – the required pressure This can either be standard site steam pressures or an individual consideration of the desired final temperature within the process vessel. The flow rate of steam at the desired pressure can be calculated for all the duties and from the above the overall heat duty for the system can be ascertained. Allowance should be made for heat losses in the distribution system and for future expansion of the system

Nitrogen The flowrate of purging can be calculated. The volumetric flow rate for this duty can be found by using the batch cycle time. The volumetric flow rate at the distribution pressure also can be calculated.

The system will normally have an accumulator depending upon the critical nature of the uses to which it is put an the method of producing nitrogen. The supply pressure will be reduced within the plant to give the variety of pressures required. There is usually a relief valve after the pressure-reducing valve to protect downstream equipment from an overpressure within the nitrogen system.

The main criteria are: – Pressure required at end user and supply – Quality – Quantity – Temperature at user – application

Compressed air The ratio of the maximum to minimum capacity of the utility is known as the turn down ratio. All systems should have the capacity to be turned down if part of the plant is under maintenance or if the process is changed for any reason. To allow the future expansion, new systems should not be designed to be operating at their peak loading for 24 hours a day.

Duty/ Standby Critical systems should have a duty standby facility such that some of the equipment is not run continuously. This allows time for maintenance without the necessity for shutdown periods.