Cleaning validation of Pharmaceutical Equipments

1.Principle:

1.  Contamination of pharma products and active pharmaceutical ingredients (APIs) can be due to cleaning agents or microorganisms or by airborne particles, raw materials, lubricants or dust. Most of the times same equipment is used for processing various products. Hence, to overcome the contamination as mentioned proper cleaning procedures are to be followed.
2. Manufacturing process should be carried and designed in a way to reduce contamination. Cleaning procedures should be followed and executed with proper validation methods.
3. Cleaning validation methods are the documented evidences that are approved and reliable procedures for equipment’s which are suitable in processing of pharma products and active pharmaceutical ingredients and further to omit analytical monitoring.

2.Scope:

1. Cleaning procedures are used for the removal of contaminants due to previous products and residues due to sanitizers and also to reduce microbial contaminants.
2. These cleaning procedures are applicable in manufacturing of pharma products and active pharmaceutical ingredients (APIs).

1. General
   1. Cleaning procedures are normally used only when the product comes in contact with the surface of equipment. Sometimes the product may migrate into non- contact parts like seals, mixing shaft, heating elements, fans of ovens and flanges etc.
   2. In case of products that are marketed cleaning procedures should be validated when there is change in products.
   3. In a batch- to- batch production it may not be mandatory to clean after every batch but the cleaning methods and cleaning intervals should be determined.
   4. While evaluating a cleaning process certain questions should be addressed like:

• At which point in operation should the equipment be cleaned?
• What is meant by ‘Visually clean’?
• Should the equipment be scrubbed by hand?
• What is accomplished when the equipment is scrubbed by hand rather than a solvent wash?
• How does cleaning process manually vary from product to product and batch to batch?
• What are the most appropriate solvents or detergents?
• Do different products in contact within equipment require different cleaning process?
• At what frequency should the cleaning process be done in order to ensure proper cleaning of each piece in equipment?
  1. Cleaning procedures for similar products and processes need not be validated individually. A representative range of products and processes which are similar can be concerned to justify a validation program addressing the main issues related to the processes and products. Further a practice called bracketing can be followed where a single validation study can be carried out by taking into account all the relevant criteria of a worst case.
  2. To prove that a method is validated cleaning procedure should be performed for three consecutive times successfully.
  3. Raw materials can be sourced from different suppliers which differ in physical properties and purity profiles and this should be considered when cleaning procedures are designed.
  4.      Revalidation should be considered in circumstances like:
     1. Revalidation while equipment, process or product changes.
     2. Periodic revalidation at defined time intervals.
  5.      When compared to clean-in-place systems, manual methods should be frequently reassessed.
  6. The concept of “test until clean” involves cleaning, sampling, testing until a acceptable residue limit is attained. This practice is not acceptable for system or equipment with a validated cleaning process and is not required to replace the need to cleaning procedures.
  7. Instead of toxic or hazardous substances, products which alter the physicochemical properties of the substance to be removed can be used.

4.Documentation

1. A Cleaning Validation Protocol is necessary to provide detailed procedure on how the cleaning process should be validated covering the following :

• Objective of the validation process;
• Roles and responsibilities while approving and performing validation study;
• Equipment description;
• Time interval between ending of production and beginning of cleaning procedures;
• Cleaning procedures to be followed for each product or manufacture system or each piece of equipment;
• Frequency of cleaning cycles to perform;
• Any monitoring equipment;
• Sampling procedures justifying their use;
• Clearly outlined sampling locations;
• Appropriate data on recovery studies;
• Analytical methods with limits of detection and quantitation for those methods;
• Acceptance criteria justifying their rationale of specific limits;
• Planned validation according to the concept of bracketing for products, equipment’s or processes
• When revalidation is needed.

1. Plant Management should approve the Cleaning Validation Protocol so that procedures laid down in the protocol are accepted and followed. In the approval of reports and protocols quality assurance should be followed.
2.  A report of Final validation should drafted concluding whether the cleaning process is validated successfully and limitations when following the protocol. This report should be approved by the Plant Management.
3. Cleaning process should be drafted in an SOP.
4. Records of the cleaning performed should be stored in a way so they are readily available providing information on the following.

• The area or piece of equipment cleaned;
• The person in charge of cleaning;
• Time when the cleaning was done;
• SOP which defines the cleaning process;
• Details of the product which was previously processed on the equipment cleaned.

1. The cleaning record should be signed by the operator involved in cleaning and person in the production and reviewed finally by Quality Assurance.

5.Personnel

1. Training should be given to the operators who are involved in cleaning on how to apply the validated cleaning procedures. Record should be maintained in the training that is carried out.
2. It is a tedious process to validate manual therefore periodic checking should be on the operators who are involved in manual cleaning procedures.

6.Equipment

1. The equipment’s design should be examined carefully identifying the hardest areas to clean particularly in semi-automatic or fully automatic clean-in-place systems.
2.  Proper equipment’s should be used when products like gummy or tarry residues are used in bulk manufacturing or in case of bags in fluid bed dryers or products with high safety risk like biologicals or highly potent products which are difficult to detect below an acceptable limit.

7.Microbiological Aspects

1. To prevent microbial contamination conditions like moisture, rough surfaces, temperature, crevices and storage time should be monitored.
2. Validation of cleaning procedures should clearly outline the storage conditions of equipment before cleaning and time between cleaning and using the equipment again so that the microbial proliferation is not allowed during cleaning and storage.
3.  After cleaning there should not be any stagnant water in the equipment and it should be stored in dry condition.

8.Sampling

1. Sampling should be done according to Cleaning Validation Protocol.
2. Two methods of sampling are accepted. They are: Direct surface sampling (swab method) and indirect sampling (use of rinse solutions). Generally the methods are used in combination to give the desired result.

• Direct Surface Sampling – the suitability of the material used and sampling medium for sampling should be determined. Recovery of samples may be affected by the choice of sampling material.
• Rinse Samples - they allow for sampling of a large surface area. Inaccessible areas of equipment which can’t be disassembled frequently can be evaluated. The solubility of the contaminant should be considered. The residue of the product or the contaminant in the solvent should be measured when rinse samples are used in cleaning validation process.

9.Detergents

1. Cleaning procedures should be evaluated for the removal of detergent residues. After cleaning acceptable limits should be determined. In ideal situations, no residues should be detected and detergent breakdown during the process should be considered.
2. Detergent composition should be known to the manufacturer and when it can’t be determined then the detergent with known composition should be considered. If there are any changes in the formulation of the detergent then it should be notified to the manufacturer.

10.Analytical Methods

1. Before carrying out Cleaning Validation Study analytical methods should be validated.
2. The analytical methods that detect residuals or contaminants should be specific to the substance to be assayed providing sensitivity which reflects the level of cleanliness acceptable by the company.
3. The analytical methods together with the sampling methods should be used so from equipment’s surface the contaminant can be recovered and to depict the level and consistency of the recovery. Poor sampling techniques result in negative results.

11.Establishment of Limits

1. Based on the materials involved and their therapeutic dose, a company should provide rationale in selecting limits and product residues.
2. The approach for setting limits can be:

• Product specific Cleaning Validation for all products,
• Grouping into product families and choosing a ‘worst case’ product,
• Grouping into groups of risk (e.g. very soluble products, similar potency, highly toxic products, difficult to detect).
  1. product residues carried over should meet certain criteria like
• Not more than 0.1% of the normal therapeutic dose of any product should appear in the maximum daily dose of following product,
• Not more than 10ppm of any product should appear in another product,
• After cleaning procedures are done no residue should be on the equipment. The concentration of the most active ingredients should be determined by the spiking studies,
• Analytical methods should provide the limit of detection below the actual limit for penicillin’s, potent steroids, allergenic ingredients and cytotoxics. Dedicated plants should be used for these products.
  1. The condition where contaminate will be uniformly distributed throughout the system can’t be ensured. An assumption where the residual contaminant would worn off from the equipment surface uniformly or occurring of contamination only at the beginning of the batch is invalid.
  2. When residual limits are established it may not be adequate to focus only on the principle reactant as chemical variations may occur which are difficult to eliminate.

Equipment, analytical methods, cleaning, revalidation, contamination

• cleaning validation. health sciences authority. http://www.hsa.gov.sg/content/dam/hsa/hprg/manufacturing_importation_distribution/overview_framework_policies/guide-mqa-008-008.pdf. published january 2013. accessed june 2016.