Manufacturing - Bulk and Sterile

Manufacturing - Bulk and Sterile Various surveys and statistical data on manufacturing or bulk compounding in hospitals revealed that a significant number of hospital pharmacies operate manufacturing program. Apart from sterile manufacture of large volume fluids and other parenterals, hospital can manufacture non-sterile liquid, oral preparation, externals and bulk preparations. The decisions of manufacturing or purchasing the drugs depend on many factors which are as follows:

Control and budget or budgetary control or economical consideration In order to develop adequate budgetary control over the manufacturing program, the hospital pharmacist is required to give lengthy consideration to his inventory and consumption rate for the finished product, raw materials requirements, manufacturing capacity, available personnel and operating costs.

Manufacturing requirements For manufacturing requirement the consumption rate for each item is calculated by reviewing the previous records and comparing this figure with the present requirement.

Material requirements Once the hospital pharmacist has determined what products he intends to manufacture and in what volume and quantity, he must next arrange for the procurement of the necessary supplies. These supplies should include items such as containers, labels and ancillary materials such as filter paper, filter pads, boxes and special labels in addition to raw materials. The materials required for manufacturing can be determined by various formulae. The quantity of a particular raw-material or the packaging material is calculated by different formulae and recorded on a summery sheet.

Manufacturing capacity Manufacturing capacity depends on the availability of equipment and economy of hospital to fulfill the requirement. The selection of equipment is made only on the basis of multiple user system. This prevents accumulating of costly equipment unless otherwise required.

Manufacturing equipment and its sources The type and size of manufacturing equipment required in a hospital depends upon manufacturing program, like the quantities to be produced, duration of production time, availability of physical facilities and the availability of persons.

Manufacturing stuff Personnel represent one of the most important considerations in a bulk compounding program. Too many personnel will raise the cost of a manufactured product to the point where it would be more economical to purchase it from a commercial supplier and too little help may mean the inability to maintain an adequate production schedule and potential errors – neither of which may be condoned. The manufacturing section must always be supervised by technically competent and legally qualified pharmacists who will support technical and non-technical persons.

Operating cost Operating cost include both direct cost, i.e., labor, cost of material etc. and indirect cost like maintenance of building, insurance policies, space maintenance etc.

Sterile manufacture Personnel requirement Personnel selected for sterile preparations should strictly follow GMP requirements and should be trained for aseptic techniques with the help of continuous education programs.

Following are some precautions and requirements of personnel in aseptic area They should be of good health and free from any dermatological conditions that might increase microbial contamination. They must have some knowledge about the basic principles of aseptic process. Movements within the room should be minimum and in and out movements are restricted during filling operations.

Cont… Every individual shall use fresh sterile uniform after every break period. Uniform consist of overalls for both men and women, hoods to completely cover the hair, face mask, plastic shoes, sterile rubber gloves, goggles. An air shower is also used for personnel to remove any loose shreds. Talking inside the room should be minimum. Things and articles on floor should not be picked up to avoid contamination.

Preparation of large and small volume parenterals The volume of injectable fluids vary greatly from fractions of milliliter to several hundred milliliter. Intravenous fluids vary from one ml to 500 ml or more than 500 ml. Intravenous fluids of 500 ml and above are called as large volume parenterals (LVP).

Facilities and requirements For sterile manufacture following equipments are necessary to meet the requirements of Drugs and Cosmetics Act. Storage equipment for ampoules and vials Storage cabinets Water still Ampoule washing machine Ampoule drying machine Filling and sealing unit Sintered glass funnel Filter press Hot air oven Equipments for evaluation and quality control Autoclave Labeling and packing units

Manufacturing area Manufacturing facilities include maximum degree of cleanliness in aseptic filling rooms, while as surrounding areas provide a buffer area in which standards of cleanliness are slightly lower than those maintained in aseptic rooms. For construction, it requires best material and design. The ceiling, walls and floors should be constructed of materials which are easy to clean and non-porous so as to prevent accumulation of dust and moisture.

Cont… One of the best materials for the floor is ceramic plastic cement applied as a thick coat on existing floor to give continuous sealed surface. Glass is generally used for partitioning and for good supervisory view of manufacturing unit.

Environmental control The standards of environmental control may vary depending upon the area involved, the processing etc. It requires good environmental control prior and during processing.

Traffic control Environment control can be maintained easily if there is no in and out traffic of supplies and persons. They should be permitted to enter aseptic areas only after following the prescribed procedures like changing of cloths, washing their hands, putting on gloves, shoes hats and face mask. Once they enter the aseptic area, they are not permitted to move out of the area till the manufacturing cycle is completed. Unauthorized persons should not be permitted into aseptic area.

Maintenance Generally cleaning is done at the end of working day or during night. It includes all the surface like ceiling, walls, floors, counters, equipments etc. Cleaning should never be done just prior to the beginning of the production process so as to permit the settling of dust from air and allow for the completion of action of disinfectants and UV radiations.

Disinfection All the surfaces should be disinfected in aseptic area and effective liquid disinfectant should be sprayed or wiped on as surfaces.

Irradiation UV rays are anti-bacterial in action, hence they produce a disinfectant action on directly irradiative surfaces. Direct irradiation of room is done when personnel are not present. It acts as a good source of reducing the bacterial count on the working benches and floors. Lamps are installed above head level so that persons present are not irradiated and only irradiate circulating air to reduce the bacterial count during processing. The best practice is to use UV light rays in the cold cathode mercury vapor lamp which provides a high proportion of radiation.

Air cleaning The air in the aseptic area can be one of the greatest sources of contamination, so to maintain the aseptic conditions besides the various precautions followed, it is extremely necessary to clean the air before it is allowed to enter into the aseptic area. Clean rooms are generally classified into two categories: Conventional clean room systems Laminar flow clean room systems

Conventional clean room systems The term conventional clean room is applied where a lesser degree of cleanliness such as class 10,000 clean room, which is defined as an environment containing not more than 10,000 particles per cubic feet of 0.5 micrometers and larger size.

Air flow pattern for "Turbulent Cleanroom"

Laminar flow clean room systems Laminar air flow provides a total sweep of a confined area because the entire body of air moves with uniform velocity along the parallel lines, originating through HEPA filters occupying one entire site of the confined area. Therefore, it baths the entire area with a very clean air, sweeping away the contaminants. The effective air velocity is 100±20 ft./min.

Air flow pattern for "Laminar Flow Cleanroom"

Advantages of laminar air flow system over conventional clean room system The Laminar air flow system offers various advantages over a conventional clean room system which are as follows: The persons working in the area does not feel the movement of the air or chill. Any part of the room can be utilized without any restriction. As the body of the air moves with a uniform velocity along the parallel lines, the capacity to carry the dust particles is more as compared to the conventional clean room system.

With the velocity of the air being 100 ft With the velocity of the air being 100 ft./min, the possibility of formation of dust particles is negligible as it does not permit the setting of dust particles. There are as many as 100 air changes per hour cubic feet which enables lesser dust pockets with less maintenance cost.

Cont… The sterile area attained is of vary high order. Thus no chemical means of sterilization is needed. Unlike the conventional air flow system, the humidity, dust and temperature are regulated as separate entities reducing the load on the filters and it required cooling and heating equipments may be separately employed to maintain a constant temperarure.

Summery Manufacturing - Bulk and Sterile Control and budget or budgetary control or economical consideration Manufacturing requirements Material requirements Manufacturing capacity Manufacturing equipment and its sources Manufacturing stuff Operating cost Sterile manufacture Personnel requirement Preparation of large and small volume parenterals Advantages of laminar air flow system over conventional clean room system