1. General:–

1.1. The processing of dry materials and products creates problems of dust control and cross-contamination. Special attention is, therefore, needed in the design, maintenance and use of premises and equipment in order to overcome these problems. Wherever required, enclosed dust control manufacturing systems shall be employed.

1.2. Suitable environmental conditions for the products handled shall be maintained by installation of air conditioning, wherever necessary. Effective air extraction systems, with discharge points situated to avoid contamination of other products and processes shall be provided. Filters shall be installed to retain dust and to protect the factory and local environment.

1.3. Special care shall be taken to protect against subsequent contamination of the product by particles of metal or wood. The use of metal detector is recommended. Wooden equipment shall be avoided. Screens, sieves, punches and dies shall be examined for wear and tear or for breakage before and after each use.

1.4. All ingredients for a dry product shall be sifted before use unless the quality of the input material can be assured. Such sifting shall normally be carried out at dedicated areas.

1.5. Where the facilities are designed to provide special environmental conditions of pressure

Differentials between rooms, these conditions shall be regularly monitored and any deviation shall be brought to the immediate attention of the Production and Quality assurance departments.

1.6. Care shall be taken to guard against any material lodging and remaining undetected in any

Processing or packaging equipment. Particular care shall be taken to ensure that any vacuum, compressed air or air-extraction nozzles are kept clean and that there is no evidence of lubricants leaking into the product from any part of the equipment.

1.7. Where different products are manufactured at the same time, in different areas or cubicles, in a multiproduct Oral Solid Dosage (OSD) manufacturing site, measures shall be taken to ensure that dust cannot move from one cubicle to another.

1.8. Correct directional air movement and a pressure cascade system can assist in preventing cross-contamination. The pressure cascade shall be such that the direction of airflow is from the clean corridor into the cubicles, resulting in dust containment.

1.9. The corridor shall be maintained at a higher pressure than the cubicles, and the cubicles at a higher pressure than atmospheric pressure.

1.10. Highly potent products shall be manufactured under a pressure cascade regime that is negative relative to atmospheric pressure.

1.11. The pressure cascade for each facility shall be individually assessed according to the product handled and level of protection required.

1.12. Building structure shall be given special attention to accommodate the pressure cascade design.

1.13. Ceilings and walls, close fitting doors and sealed light fittings shall be in place, to limit ingress or egress of air.

1.14. The pressure differential between adjacent rooms could be considered a critical parameter,

Depending on the outcome of risk analysis. The limits for the pressure differential between adjacent areas shall be such that there is no risk of overlap in the acceptable operating range, e.g., 5 Pa to 15 Pa in one room and 15 Pa to 30 Pa in an adjacent room, resulting in the failure of the pressure cascade, where the first room is at the maximum pressure limit and the second room is at its minimum pressure limit.

1.15. Low pressure differentials may be acceptable when airlocks (pressure sinks or pressure bubbles) are used to segregate areas.

1.16. The effect of room pressure tolerances shall be calculated and taken into consideration.

1.17. The pressure control and monitoring devices used shall be calibrated and qualified. Compliance with specifications shall be regularly verified and the results recorded. Pressure control devices shall be linked to an alarm system set according to the levels determined by a risk analysis.

1.18. Manual control systems, where used, shall be set up during commissioning, with set point marked, and shall not change unless other system conditions change.

1.19. Airlocks can be important components in setting up and maintaining pressure cascade systems and also to limit cross-contamination.

1.20. Airlocks with different pressure cascade regimes include the cascade airlock, sink airlock and bubble airlock:-

(a) Cascade airlock: higher pressure on one side of the airlock and lower pressure on the other;

(b) Sink airlock: lower pressure inside the airlock and higher pressure on both outer sides; and

(c) Bubble airlock: higher pressure inside the airlock and lower pressure on both outer sides.

1.21. Doors shall open to the high pressure side, so that room pressure assists in holding the door closed and in addition self-closers shall be provided. If the doors open to the low pressure side, the door closer springs shall be sufficient to hold the door closed and prevent the pressure differential from pushing the door open. There shall be a method to indicate if both doors to airlocks are open at the same time, or alternatively these shall be interlocked. The determination of which doors shall be interlocked shall be the subject of a risk assessment study.

1.22. Central dust extraction systems shall be interlocked with the appropriate air-handling systems, to ensure that they operate simultaneously.

1.23. Room pressure differential between adjacent cubicles, which are linked by common dust extraction ducting, shall be avoided.

1.24. Air shall not flow through the dust extraction ducting or return air ducting from the room with the higher pressure to the room with the lower pressure (this would normally occur only if extract or return systems were inoperative). Systems shall be designed to prevent dust flowing back in the opposite direction in the event of component failure or airflow failure.

1.25. Adequate room pressure differential indication shall be provided so that each critical room pressure can be traced back to ambient pressure (by summation of the room pressure differentials), in order to determine the room actual absolute pressure. Room pressure indication gauges shall have a range and graduation scale which enables the reading to accuracy, as appropriate; normal operating range, alert and action limits shall be defined and displayed at the point of indication. A colour coding gauge may be helpful.

Room pressure indication may be either analogue or digital, and may be represented as either pressure differentials or absolute pressures. Whichever system is used any out-of-specification condition shall be easily identifiable.

1.26. Material Pass-Through-Hatches (PTH) or Pass Boxes (PB) can also be used for separating two different zones. PTHs fall into two categories, namely a dynamic PTH or a passive PTH. Dynamic PTHs have an air supply to or extraction from them, and can then be used as bubble, sink or cascade PTHs.

1.27. Where appropriate, temperature and relative humidity shall be controlled, monitored and recorded, where relevant, to ensure compliance with requirements pertinent to the materials and products and provide a comfortable environment for the operator where necessary.

1.28. Maximum and minimum room temperatures and relative humidity shall be appropriate. Alert and action limits on temperatures and humidity shall be set, as appropriate.

1.29. The operating band or tolerance between the acceptable minimum and maximum temperatures shall not be made too close. Tight control tolerances may be difficult to achieve and can also add unnecessary installation and running costs.

1.30. Cubicles or suites, in which products requiring low relative humidity are processed, shall have well sealed walls and ceilings and shall also be separated from adjacent areas with higher relative humidity by means of suitable airlocks.

1.31. Precautions shall be taken to prevent moisture migration that increases the load on the HVAC system.

1.32. Humidity control shall be achieved by removing moisture from the air, or adding moisture to the air, as relevant.

1.33. Dehumidification (moisture removal) may be achieved by means of either refrigerated

Dehumidifiers or chemical dehumidifiers.

1.34. Duct material in the vicinity of the humidifier shall not add contaminants to air that will not be removed by filtration further downstream.

1.35. Air filters shall not be installed immediately downstream of humidifiers, as moisture on the filters could lead to bacterial growth.

1.36. Cold surfaces shall be insulated to prevent condensation within the clean area or on air-handling components.

1.37. When specifying relative humidity, the associated temperature shall also be specified.

1.38. Chemical driers using silica gel or lithium chloride are acceptable, provided that they do not become sources of contamination.

1.39. Wherever possible, dust or vapour contamination shall be removed at source. Point-of-use

extraction, i.e., as close as possible to the point where the dust is generated, shall be employed. Spot ventilation or capture hoods may be used as appropriate.

1.40. Point-of-use extraction shall be either in the form of a fixed high velocity extraction point or an articulated arm with movable hood or a fixed extraction hood.

1.41. Dust extraction ducting shall be designed with sufficient transfer velocity to ensure that dust is carried away and does not settle in the ducting. Periodic checks shall be performed to ensure that there is no build-up of the dust in the ducting.

1.42. The required transfer velocity shall be determined on the density of the dust (the denser the dust, the higher the transfer velocity shall be, e.g., 15–20 m/s).

1.43. Airflow direction shall be carefully chosen to ensure that the operator does not contaminate the product and also so that the operator is not put at risk by the product.

1.44. Point extraction alone is usually not sufficient to capture all of the contaminants, and general

directional airflow shall be used to assist in removing dust and vapours from the room.

1.45. Typically, in a room operating with turbulent airflow, the air shall be introduced from ceiling

diffusers, located at the door entry side of the room and extracted from the rear of the room at low level to help give a flushing effect in the room. Correct flushing of the rooms may be verified by airflow visualization smoke tests.

1.46. When dealing with particularly harmful products, additional steps, such as handling the products in glove boxes or using barrier isolator technology, shall be used.

1.47. Exhaust air discharge points on pharmaceutical equipment and facilities, such as from fluid bed driers and tablet-coating equipment, and exhaust air from dust extraction systems, carry heavy dust loads and shall be provided with adequate filtration to prevent contamination of the ambient air.

1.48. Where the powders are not highly potent, final filters on a dust exhaust system shall be fine dust filters with a filter classification of 5μ.

1.49. Where reverse-pulse dust collectors are used for removing dust from dust extraction systems, they shall usually be equipped with cartridge filters containing a compressed air lance, and be capable of continuous operation without interrupting the airflow.

1.50. Mechanical-shaker dust collectors shall not be used for applications where continuous airflow is required, in order to avoid unacceptable fluctuations in room pressures, except in the case where room pressures are automatically controlled.

1.51. When wet scrubbers are used, the dust-slurry shall be removed by a suitable means, e.g., a drainage system or waste removal contractor.

1.52. The quality of the exhaust air shall be determined to see whether the filtration efficiency is adequate with all types of dust collectors and wet scrubbers.

1.53. Where necessary, additional filtration may be provided downstream of the dust collector.

1.54. The systems for fume, dust and effluent control shall be designed, installed and operated in such a manner that they do not become possible sources of contamination or cross-contamination, e.g., an exhaust air discharge point located close to the HVAC system fresh air inlet.

1.55. Fumes shall be removed by means of wet scrubbers or dry chemical scrubbers (deep-bed scrubbers).

1.56. Wet scrubbers for fume removal normally require the addition of various chemicals to the water to increase the adsorption efficiency.

1.57. Deep-bed scrubbers shall be designed with activated carbon filters or granular chemical adsorption media. The chemical media for deep-bed scrubbers shall be specific to the effluent being treated.

1.58. The type and quantity of the vapours to be removed shall be known to enable the appropriate filter media, as well as the volume of media required to be determined.

1.59. There shall be no risk of contamination or cross-contamination (including by fumes and volatiles) due to recirculation of air.

1.60. Depending on the airborne contaminants in the return air system it may 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.

1.61. HEPA filters may not be required where the air handling system is serving a single product facility and there is evidence that cross-contamination would not be possible.

1.62. Re–circulation of air from areas where pharmaceutical dust is not generated such as secondary packing may not require HEPA filters in the system.

1.63. HEPA filters may be located in the air handling unit or placed terminally. Where HEPA filters are terminally mounted they shall preferably not be connected to the ducting by means of flexible ducting. Due to the high air pressure required for the terminal filter; this connection shall preferably be a rigid duct connection. Where flexible ducting is used, it shall be as short as possible and properly fixed to withstand duct pressure.

1.64. Air containing dust from highly toxic processes or solvents or flammable vapours shall never be recirculated to the HVAC system.

1.65. Adequate airlocks, such as personnel airlocks (PAL), material airlocks (MAL), change rooms and passages shall be provided to protect passage between different cleanliness conditions. These shall have supply and extract air systems as appropriate.

1.66. Areas such as airlocks, change rooms and passages, shall be designed so that the required pressure cascades can be achieved.

1.67. Detailed diagrams depicting pressure cascades, air flow directions and flow routes for personnel and materials shall be prepared and maintained.

1.68. Where possible, personnel and materials shall not move from a higher cleanliness zone to a lower cleanliness zone and back to a higher cleanliness zone; (if moving from a lower cleanliness zone to a higher cleanliness zone, changing or decontamination procedures shall be followed).

1.69. The final stage of the changing room shall, in the “at rest” state, be the same good manufacturing practices classification grade as the area into which it leads.

2. Sifting, mixing and granulation:–

2.1. Unless operated as a closed system, mixing, sifting and blending equipment shall be fitted with dust extractors or in a dedicated area for each operation.

2.2. Residues from sieving operations shall be examined periodically for evidence of the presence of unwanted materials.

2.3. Critical operating parameters like time and temperature for each mixing, blending and drying operation shall be specified in a Master Formula, monitored during processing, and recorded in the batch records.

2.4. Filter bags fitted to fluid-bed-drier shall not be used for different products, without being washed in between use. With certain highly potent or sensitizing products, bags specific to one product only shall be used.

Air entering the drier shall be filtered. Steps shall be taken to prevent contamination of the site and local environment by dust in the air leaving the drier due to close positioning of the air-inlets and exhaust.

2.5. Granulation and coating solutions shall be made, stored and used in a manner which minimizes the risk of contamination or microbial growth.

3. Compression (Tablets):–

3.1. Each tablet compressing machine shall be provided with effective dust control facilities to avoid cross contamination. Unless the same product is being made on each machine or unless the compression machine itself provides its own enclosed air controlled environment, the machine shall be installed in separate cubicles.

3.2. Suitable physical, procedural and labelling arrangements shall be made to prevent mix up of materials, granules and tablets on compression machinery.

3.3. Accurate and calibrated weighing equipment shall be readily available and used for in-process monitoring of tablet weight variation. Procedures used shall be capable of detecting out of limits tablets.

3.4. At the commencement of each compression run and in case of multiple compression points in a compression machine, sufficient individual tablets shall be examined at fixed intervals to ensure that a tablet from each compression station or from each compression point has been inspected for suitable Pharmacopoeial parameters like “appearance”, “weight variation”, “disintegration”, “hardness”, “friability” and “thickness”. The results shall be recorded as part of the batch documentation.

3.5. Tablets shall be de-dusted, preferably by automatic device and shall be monitored for the presence of foreign materials besides any other defects.

3.6. Tablets shall be collected into clean, labelled containers.

3.7. Rejected or discarded tablets shall be isolated in identified containers and their quantity recorded in the Batch Manufacturing Record.

3.8. In-process control shall be employed to ensure that the products remain within specification. During compression, samples of tablets shall be taken at regular intervals of not greater than thirty minutes to ensure that they are being produced in compliance with specified in-process specification.

The tablets shall also be periodically checked for additional parameters such as “appearance”, “weight variation”, “disintegration”, “hardness”, “friability” and “thickness” and contamination by lubricating oil.

4. Coating (Tablets):–

4.1. Air supplied to coating pans for drying purposes shall be filtered air and of suitable quality. The area shall be provided with suitable exhaust system and environmental control (temperature and humidity) measures.

4.2. Coating solutions and suspensions shall be made afresh and used in a manner which shall minimise the risk of microbial growth. Their preparation and use shall be documented and recorded.

5. Filling of Hard Gelatin Capsule:– Empty capsules shells shall be regarded as “drug component” and treated accordingly. They shall be stored under conditions which shall ensure their safety from the effects of excessive heat and moisture

6. Printing (Tablets and Capsules):–

6.1. Special care shall be taken to avoid product mix-up during any printing of tablets and capsules. Where different products or different batches of the same product, are printed simultaneously, the operations shall adequately be segregated. Edible grade colours and suitable printing ink shall be used for such printing.

6.2. After printing, tablets and capsules shall be approved by Quality Control before release for packaging or sale.

7. Packaging (Strip and Blister):–

7.1. Care shall be taken when using automatic tablet and capsule counting, strip and blister packaging equipment to ensure that all “rogue” tablets, capsules or foils from packaging operation are removed before a new packaging operation is commenced. There shall be an independent recorded check of the equipment before a new batch of tablets or capsules is handled.

7.2. Uncoated tablets shall be packed on equipment designed to minimise the risk of cross-contamination. Such packaging shall be carried out in an isolated area when potent tablets or Beta lactum containing tablets are being packed.

7.3. The strips coming out of the machine shall be inspected for defects such as misprint, cuts on the foil, missing and improper sealing.

7.4. Integrity of individual packaging strips and blisters shall be subjected to vacuum test periodically to ensure leak proofness of each pocket strip and blister and records maintained.

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