Pharma Facility: Need for properly designed Cleaning Systems

In India, majority of the Pharma manufacturing facilities handle multiple products and 80% of the facilities manufacture Oral Solid Dosage forms, i.e. Tablets and Capsules. These products share common equipment in the facilities thus increasing the potential for cross contamination. Therefore, every manufacturing process has to be followed by an efficient cleaning procedure and it is imperative to have a well-defined and validated cleaning system in place in order to prevent the cross contamination of the products.

Two important aspects to be considered for achieving efficient cleaning include:

• Selection of Equipment Design: The design of the equipment should be such that it lends itself for easy cleaning such as smooth impervious surface and good material of construction like polished stainless steel that can withstand cleaning with various detergents and solvents.
• Use of automated tailor-made Cleaning Systems for consistency in cleaning of the equipment.

Western countries also use the same technologies as used in India. In India, experts pinpoint that the pharma company decides what level of cleaning is required and how to go about it. SOPs are laid down accordingly based on the available methods and technologies.

Technologies and Trends

Clean-In-Place system (CIP) is highly desirable and most of the drug manufacturing equipment nowadays has this system in place. The cleaning procedure is inbuilt. There are standalone or external equipment – known as COP equipment, in which all parts of the equipment can be dismantled for application of cleaning procedures.

For each and every equipment, it is important to identify hard to reach and hard to clean surfaces. If the part can be dismantled that should be the first preference, if not, suitable modification to the cleaning procedure is required that may include use of specially designed tools such as long handle brushes, use of pressure guns with specially designed spray nozzles etc.

Says S. M. Mudda, Director – Technical & Operations, Micro Labs, Bangalore, Out of the four major sources of cross contamination i.e. Airborne Transfer, Mix-up, Mechanical Transfer and Chemical Residue from the equipment, the residue from previous product entering into another product inadvertently beyond unacceptable limits poses a major challenge for cleaning of the equipment in a multi-product facility. You require an efficient cleaning system which is automated and validated one to ensure that you are able to clean the equipment to the desired level consistently. However if you do it manually, consistency in cleaning may not always be possible.”

The global trend therefore, besides having a CIP, is to lay emphasis on designing GMP-compliant equipment. Design of the equipment is such that there are no hard to clean areas. There is no possibility of retention of residue also. The material is of stainless steel and the equipment has polished surfaces and good engineering design.

Cleaning Work Flow in Drug manufacturing unit

Echoing similar views, YA Chowdary, Executive Vice-President-Operations, Medreich Limited, Bangalore, says, Cleaning of the equipment in a pharmaceutical industry plays a very important role in eliminating the cross contamination. In order to ensure proper cleaning of the equipment, one should develop a suitable cleaning method which can remove the traces of the previous product and validate the cleaning method to verify the adopted method is capable of giving expected results.

An appropriate cleaning method need to be developed for the cleaning of the equipment based on the type and the design of the equipment. Though the equipment cleaning procedure may differ between two batches of the same product and between two different products, we are mainly discussing about the cleaning of equipment between one product to another product. Let us take an example of a cleaning procedure of an equipment and validation of it. Rapid Mixing Granulator (RMG) is an equipment used mainly in the manufacturing of tablet dosage forms. To clean the equipment, initially the equipment is dismantled and the removable parts are separated from the machine.

The parts and the equipment are initially cleaned with raw water from a high pressure jet to remove the adhered material. Later the equipment and the parts are cleaned by using a cleaning agent – 0.1% Sodium Lauryl Sulphate (which is a food grade material and widely used as a pharmaceutical excipient in the formulations) with a scrubber. Usually the cleaning agent selected should be easily removable, food grade and the detergent used should give information to derive the acceptable limit based on scientific rationale. After the completion of the cleaning with the cleaning agent, the machine & the parts are thoroughly cleaned with adequate raw water with high pressure jet to remove any traces of the cleaning agent. Some times even hot water is also used for these purposes. Once the equipment is thoroughly cleaned finally the parts and the entire equipment is cleaned with purified water. This purified water is made through Reverse osmosis / De-ionization techniques to meet the pharmacopoeial standards. The same procedure is used to clean the entire area and the surface of the machine. Finally the equipment is dried with a reusable non shredding cloth. Dupont is one of the leading manufacturer of the cloth.

Steam Cleaning

Clean steam is used in the pharmaceutical industries in processes where the steam or its condensate can come into contact with a pharmaceutical or medical product and cause contamination. In such cases, steam from a conventional boiler (often called utility or plant steam) is unsuitable because it may contain boiler additives, rust or other undesirable materials. The use of clean steam is determined by the rules of Good Manufacturing Practice (GMP). These are general rules applicable to pharmaceutical manufacture, detailed in the Code of Federal Regulations. They do not provide any specific recommendation regarding steam, but do present the general requirements of facilities, systems, equipment and operation needed to prevent contamination of pharmaceutical products during their manufacture.

The main use of clean steam in manufacturing is for the sterilization of products or, more usually, equipment. Steam cleaning (sterilization) can be done in a set up which is compatible with heat. There are restrictions that design of the set up should cater to the temperature because when steam is used, the temperature of the room may go up to 80-90OC. “Being a part of the CIP, steam cleaning is also required to bring down microbial load in some manufacturing units, where all dosage forms are manufactured,” Mudda adds.

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.

1. 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.
2. 10ppm criteria: Not more than 10ppm of any product appear in the following product.
3. 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.