Pure steam must be free of contaminants at the point of use. Chemical and microbial contaminants can enter steam systems in a variety of ways, and in the design of pure steam systems this must be avoided. Pathways for contamination include leakage, air being pulled into the system and “grow through” from a contaminated external environment.
Occupational Safety
Chowdary pinpoints, “Most of the times we avoid cleaning with pure steam because it is very dangerous to handle the live steam at work place. Many accidents happen due to the steam hoses, if the handler does not handle it properly. It becomes an occupational hazard. Alternately hot water may be used for this purpose.
Maintaining Hygiene
Ravi Chandran, Manager-Quality Control, Bafna Pharmaceuticals Ltd, Chennai, says, “We are not opting to use steam cleaning in our unit”. Different companies use different methods for cleaning & sanitizing of their facility/equipment. Hydrogen Peroxide or Ozone and Sodium Hypochlorite are used to sanitize the facility and equipment. These reagents cleanses the equipment based on the ability to generate nascent Oxygen and Chloride ion, which effectively controls microbial contamination. Cleansing agents like Sodium Lauryl Sulphate (SLS) is required for eliminating the previous product residue. The main purpose is to keep microbial load / cross contamination under control.
“Exposure to these chemicals should be avoided for a certain period by the humans till the time it gets deteriorated to oxygen after cleaning when Hydrogen Peroxide or Ozone is used” he added.
Talking about the aspect of hygiene, Mudda explains that the quality of the environmental conditions depends on the basic hygiene levels followed in the facility. If we clean the area of the facility on a day to day basis with detergents, solvents and solutions and carry out mopping of the floor with suitable disinfectants, there remains no issue specifically with the microbial quality of that particular area. Fumigation and other customized solutions are also available in the market, which helps reduce contamination by microbial growth.”
Some experts however do not recommend use of any chemical during cleaning because cleaning validation study is done after the cleaning process.
Sampling Techniques and Testing Methods:
The equipment should be visually clean and it can be confirmed by physical verification. However, more scientific and quantifiable methods of sampling such as Sampling by Swab and Rinse Water Samples are used in the industry. These samples are tested for determining the residue of the previous product by validated analytical methods capable of detecting low level residues.
Cleaning validation of the equipment
Once the equipment cleaning method is developed, the cleaning method needs to be validated. Cleaning validation is a procedure to establish the documented evidence that the cleaning method used to clean the equipment is capable of removing the traces of the previous product, to a level below the acceptance criteria.
This is mainly because visually one may not be able to see the residual matter. But when a sample is taken from the product contact surface and analyzed chemically, traces may be found.
Cleaning validation has got the following phases.
First Phase – Identifying the marker compound: Several Active Pharmaceutical Ingredients (APIs) are handled in the manufacturing area and it is very difficult to do the cleaning validation on all the molecules with the established cleaning method. Because, the cleaning validation is generally carried on three consecutive cleaning activity after a particular product. Hence a worst case approach shall be considered for the selection of the API for the cleaning validation. Such identified molecule is considered as the marker compound.
Chowdary explains, “The selection of the molecules in the manufacturing area depends mainly on two worst case criteria – the API that is most difficult to wash and the API which is highly potent. One needs to identify the molecules which fall under these two categories.
Generally four molecules are selected, two molecules on the basis of most difficult to wash and the other two on the basis of the potency. Cleaning validation of three consecutive cleaning after these products needs to be studied.
Second Phase : Fixing the Maximum allowable carry over (MACO) residue: The following criteria may be used for the identification of the MACO.
- Dose criteria: Not more than 0.1% of the normal therapeutic dose of any product should appear in the daily dose of the following product.
- 10ppm criteria: Not more than 10ppm of any product appear in the following product.
- Visual criteria: No quantity of the residue should be visible after the cleaning.
Sampling techniques like Cotton swab or rinse may be used to draw the samples from the cleaned equipment surface. An area of 10cm x 10cm may be selected on the surface. The quantity obtained in this sample will be extrapolated to the total product contact surface area present in the equipment. Samples are also drawn for the microbiological evaluation. Cleaning validation needs to be subjected for the periodic review as the cleaning depends on the operator/equipment wear & tear and the unknown cleaning process variability. Ideally a frequency of once in two years is considered for the cleaning validation.
Clean room setting
Once the equipment and the area is cleaned and ready to start the activity, it is important to check the conditions that are required to perform the manufacturing activity in the area. For example, capsule and tablets manufacturing area requires controlled temperature and humidity conditions. These conditions are very important to maintain the quality and the stability of the product being manufactured.
Trend in terms of equipment
There are some equipment which are CIP because you cannot afford to move the equipment because of their heavy nature. Equipment like Rapid Mixing Granulator (RMG) and Fluid Bed Drier (FBD) are CIP equipment. Meshes and other Storage Bins are considered as the COP ones. They can be removed and cleaned separately in the dedicated washing areas. There are equipment available to clean these removable parts and the Storage Bins, which can be programmed for the washing cycles. However, such cleaning of the equipment also requires validation.
There are several washing equipment available in the market which are both indigenous as well as Imported ones. However, the indigenous ones are value for money with good performance and efficiency.
Challenge areas
Challenge areas in India are that there are requirements of good design in a equipment, good design of CIP equipment and validated automated cleaning procedures.
The cleaning validation is necessary to establish the consistency and uniformity by discussing practices that have been found acceptable. One should recognize that with cleaning validation, as with validation of other processes, there can be more than one way to validate a process. At the end, the test of any validation process is whether scientific data shows that the system consistently does as expected and produces a result that consistently meets predetermined specifications.
The main objective of cleaning validation of equipment/utensils/components is to demonstrate sufficient documented evidence to ensure that the cleaning process can consistently remove residue of the subjected product below the established acceptance criteria.
Patients shall not be exposed to more than 1/1000 of the therapeutic dose of another API (as carry over residue). Usually individual equipment/utensil and/or components are cleaned separately and are clubbed with a pre-wash and/or inspection program. Any cleaning procedure generally comprises thorough cleaning with detergents/neutralizing agents/chelants/solvents alone/in suitable combination followed with final rinsing with Purified Water or Water for Injection. The final rinse water is then tested for the pH &/or TOC &/or conductivity in conformance with pre-defined acceptance criteria.
Fundamentally, the requirements for cleaning validation & the cleaning process are almost similar for manufacturing of drug substances and drug products. Nevertheless, the cleaning process of equipment & facility for drug substances are considered to be more complex as compared to the cleaning procedure for Drug Product.
