What are alert and action limits and why they are so important in pharmaceuticals?

In pharmaceuticals alert and action limits are very important. These limits are used to have effective control over the process.
Alert Limits: Alert limits are in house limits which are defined based on the trend analysis. These limits are like a barrier before the final action limits, given by different regulatory agencies. We have to be alert if microbial count reach to this alert level. It is not necessary to take any action when count reach to alert limit level but we have to be alert as this is a trigger that something is going wrong within the environment and microbial contamination is increasing in the area.
Action Limits: Action limits are also in house limits which are defined based on the trend analysis. When microbial contamination reach to these action limits then action is mandatory to control the contamination in area otherwise if not controlled, we might get area failure. These alert and action limits must be less then the final limits defined by different guidelines and regulatory agencies. For example in case of settle plate exposure, 5 cfu's is the final limit for class B area defined by EU GMP and Drug and Cosmetic act (Schedule M). If we work on this final limit of 5 cfu's then there are chances that we may get more than 5 cfu's in class B and this results in area failure because there is no limit barrier before this final limit. But if we define in house limits like 3 cfu's for alert limit and 4 cfu's for action limits (based on trend data) then we have two barriers before the final limit and there would not be any chance of area failure because if microbial count increases and reach at this in house alert and action limit then we have lot of time to control the area by taking effective action. But if we work with final limits mentioned in guidelines then area results would be either less then 5 cfu's or more than 5 cfu's which means results would be either pass or fail. So, its better to set alert and action limits based on the trend data.

What is viable and non viable particle monitoring in pharmaceuticals?

In pharmaceutical companies monitoring of controlled area is performed by two methods. 1 Viable particle monitoring 2 Non- viable particle monitoring
In pharmaceutical companies drugs are manufactured in controlled or aseptic areas. So before going to manufacture any product we need to verify the manufacturing environment by monitoring viable and non viable particles. Viable particle monitoring: Viable particles includes bacteria, fungus and their spores and to check the number of these particles we have an environmental monitoring programme which includes Settle plate exposure (Passive air sampling), Active air sampling, Surface monitoring and Personnel monitoring methods. So monitoring of environment by these methods is called viable particle monitoring. By using these different methods we can determine the number of cfu's in particular class of area. Pharmacopoeias and regulatory agencies have defined certain limits of viable particles in these controlled area and number of colony forming units (cfu's) should be less than the final defined limits. If microbes are not with in the limits in the manufacturing area then they may cause product contamination. By using these methods and based on the observations we can assure that the number of cfu's are with in the limits and controlled area is safe for drug manufacturing. Non-viable particle monitoring: In non-viable particle monitoring we check the number of particles of 0.5 and 5.0 micron size. These particles also should be with in the limits. Particular counter is used for the non viable particle monitoring but there is a limitation of this instrument. This instrument can't differentiate between viable and non viable particle. Any particle either viable or non viable if detected by the sensor of this instrument, it will count this particle. If non viable particles increases in a particular area then there will be chance of increase in the viable particle count also because viable particles are not free floating they need a carrier to float from one area to another area. So these viable particles are carried by the non viable particles from one place to another place. So, to control a classified area we need to control both viable and non viable particles.

Why Sterility test require 14 days of long incubation time?

Sterility testing is the method to check viable contamination (bacteria, fungus, spores etc.) in the product. This testing is very important but it is time consuming. Once you tested the product, it require 14 days of long incubation time.As we know that bacteria require 3-5 days for the growth and fungus require 5-7 days for growth then why sterility incubation require 14 days? Sterile products are manufactured in aseptic environment and that environment must be suitable for the sterile product manufacturing. We perform environmental monitoring to check viable contamination in the area and to control viable contamination we perform disinfection, sanitization and fogging in the area. Personnel are also involved in the aseptic manufacturing activities and in aseptic area personnel are the main source of product contamination. Sterility testing require 14 days of long incubation time because there are some bacteria which are very slow growing like Propionibacterium acne. P.acne is gram positive, rod shaped, slow growing bacteria which is found in the acne of humans. This bacteria is associated with the humans and very slow growing and it could be the source of product contamination. So, for the recovery of these type of slow growing microorganisms, 14 days are enough to support the growth of these slow growing microorganisms if present in the product. Another reason is that in aseptic environment microorganisms could be in damaged or in injured form so it require long time for the recovery of these microorganisms in media. That's why sterility testing require 14 days of long incubation time

Bowie Dick test for Vacuum Sterilizers.

Bowie Dick test has been widely used in pharmaceutical industries for the vacuum sterilizers. This test was developed by J. H. Bowie and J. Dick. This test is perform to verify heat penetration inside the chamber. As we know that pressure and vacuum pluses are there in steam sterilizers. The purpose of pressure and vacuum pulse is to effectively remove air from the chamber because air is a bad conductor of heat and if air pockets are present inside the chamber then it would be very difficult to sterilize the load. Heat penetration can be checked by oberving class 2 chemical indicator sheet which is used for this test. If colour change of the indicator sheet is uniform then it means air has effectively removed from the chamber and no air pockets left inside the chamber during sterilization. But if colour change is not uniform then it means these pulses are not effective to remove all air and air pockets from the chamber. In the past time, bowie dick test was performed by using layer of towels having an indicator sheet inbetween the towels. These towels were placed over the drain point which would be considered as cold spot of the autoclave. But now a days this towel concept has been replaced by the bowie dick pack. Different companies provide different bowie dick test kit but the purpose of all these kits it to check heat penetration inside the load. As per HTM 2010 guideline, it is also called standard test pack. Total weight of the pack should be 7.0±0.7 kg and height of the pack should be 25 cm or 250 mm. This test has to be perfomed on daily basis as per HTM 2010 guideline.The basic principle of this test is that when we run the bowie dick cycle air is removed from the chamber and all air trapped inside the bowie dick pack which we place over the drain point of the autoclave. If air removal is effective than heat penetration will be proper and there will be unifrom colour change of the indicator sheet. And if air removal is not effective then colour change will not be uniform. There are different type of bowie dick test packs available in the market. For example one of them is a set of paper sheets in a pack and middle of these sheets there would be a chemical indicator sheet. To use this type of bowie dick pack just place the pack as such over the drain point, no need to maintain the weight and height of the pack. Another one is having a S.S holder which can hold a bunch of sheet and in the middle, indicator sheet would be there and that pack has to be placed over the drain point. This one provide the required pressure on the pack (weight) and required height is maintained by the SS holder.

Why 70% Isopropyl alcohol is used as disinfectant in pharmaceutical industries?

Iso-propyl alcohol (IPA) is widely used as a disinfectant in pharmaceutical companies . IPA is very effective on gram positive as well as gram negative bacteria. Most of the hand disinfectants available in the market contains IPA as an active component just because of its effectiveness. IPA is very effective and kill microbial cell with in a few seconds. But one limitation of IPA is that it is not effective against bacterial and fungal spores. Disinfectant efficacy depends upon two factors. First is concentration of disinfectant solution and second is contact time. Disinfectant validation activity also depends upon these two factors. In pharmaceuticals that's why validation activity must be performed to validate its effective concentration and contact time. Different guidelines and pharmacopoeias recommend 70% IPA solution because at this particular concentration, IPA is very effective. But why 70% IPA is effective and recommended by pharmacopoeias and guidelines why not 100 %? The reason is behind the mode of action of 70% IPA. Bacterial cells have proteins in their cell wall and when this protein comes in contact with the 70% IPA during disinfectant application, coagulation of proteins takes places in which denaturation of proteins occurred and after that IPA penetrate in the interior of the cell which cause lysis or death of the cell. Protein coagulation also happens in case of 100% IPA but with very fast rate and because of this very fast protein coagulation process denatured protein forms protective layer out side of the cell. When this happens, 100% can not penetrate inside the cell and not able to kill the microbe. Microorganisms become dormant in that conditions. In case of 70% IPA protein coagulation takes place with a slow rate and due to this 70% IPA get enough time to penetrate in the cell and kill the microorganism. Another factor is contact time, 70% IPA takes longer time to evaporate from any surface hence get enough contact time and in this mean time it show its efficacy but in case of 100% IPA, evaporation will be very fast, contact time will be less and it will not be so effective against microbes. That's why 70% IPA solution is used as disinfectant in pharmaceuticals industries.