Regulatory Expectations from Cleaning Validation : Pharmaguideline

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Regulatory Expectations from Cleaning Validation

FDA has specific requirements for cleaning validation from pharmaceutical manufacturers those must be fulfilled before any regulatory inspection.
Cleaning validation is an integral part of the pharmaceutical manufacturing process. A piece of equipment itself can contaminate the product if it is not cleaned properly. Improperly cleaned manufacturing equipment is a major source of cross-contamination. Regulatory agencies are more concerned about the cross-contamination of penicillin with non-penicillin products.

A number of warning letters have been issued by the FDA for deficiencies in cleaning procedures. Residues of the previous product, as well as the cleaning agent used for equipment cleaning, must be cleaned to prevent the cross-contamination.

Following are the general requirements of regulatory agencies for pharmaceutical manufacturing firms regarding cleaning validation.

1. Cleaning Procedures: A written procedure for cleaning processes for all pieces of equipment used in manufacturing. If there are different cleaning procedures for a batch to batch change and product to product change or water-soluble and water-insoluble residues, then conditions to follow the procedures should be clearly mentioned. Fluid bed dryer bags are difficult to clean so they should be dedicated to specific products.

2. Cleaning validation protocol should be written and approved before starting the validation activity. Responsibilities for the validation activity, sampling procedure, analytical method, acceptance criteria and revalidation criteria must be clearly defined in validation protocol.

regulatory expectations for cleaning validation

3. Validation must be conducted in accordance with the validation protocol. Every written step must be followed and each followed step must be written in the protocol.

4. The final report must be approved by the management with the result and conclusion of the cleaning validation activity. The conclusion should state that the residues of the previous product have been reduced to the acceptance level.

5. During an inspection, the regulatory inspectors need to be satisfied with the cleaning process and its validation. Validation should answer their question during evaluation like how the equipment is cleaned, with a scrubber or just washed with water? Was cleaning batch to batch or product to product? Which parts of the equipment were cleaned? These steps can help to develop an effective and easy procedure to clean the equipment because cleaning validation is not required between two batches of the same product and the equipment should be only visually clean in that condition.

6. Some clean-in-place systems and equipment are difficult to clean and the operators must be aware of the cleaning of these difficult to clean parts of the system and equipment.

7. Microbial aspects of the clean-in-place systems and equipment should be considered because microbial growth may occur during storage of the equipment and systems. Equipment should be properly dried after cleaning and application of 70% IPA solution may help to prevent the microbial growth during storage. A maximum storage period must be defined within which the equipment or system can be used for manufacturing.

8. If any residue is found on the cleaned equipment then it is necessary to review the cleaning procedure and operator who cleaned the equipment should be trained again for proper cleaning.

9. Specificity and sensitivity of the analytical method must be determined. HPLC can help to determine the contaminants at a very low level. If it is not possible to determine the contaminants, it doesn’t prove the absence of contaminants at all but it indicates the analytical is unable to detect the contaminants below its detection limit.

10. All contaminants present on the equipment surface cont be recovered therefore a recovery test must be carried out to get the accurate results. An inaccurate recovery factor may result in false cleaning validation.

11. Both direct surface sampling and rinse sampling are required for cleaning validation. Interference of the swab in the analysis should be determined. Surface sampling is important because water-insoluble residues and dried & hard to clean area of the equipment can be sampled easily using this technique.

12. By using of rinse sampling technique the inaccessible parts of equipment and systems can be sampled. A large surface area is sampled by rinse sampling, therefore, a very low amount of the residue can be sampled and determined.

13. Limits for cleaning validation should be established on the basis of the therapeutic dose of the product and established limits should be practical, achievable and justifiable.

14. Detergents used for cleaning must be cleaned completely. Residues of detergent are also considered as contaminants because detergent is not a part of the product. To analyze the residues of detergent, all components of detergent must be known therefore detergent s for cleaning should be selected carefully.

It is necessary to full fill the regulatory requirements to prevent the warning letter. Following are some warning letters issued due to deficiencies in cleaning process followed by the pharmaceutical manufacturing firms.
Lantech Pharmaceuticals Limited
Aurobindo Pharma Limited
Rxhomeo Private Limited
Petra Hygienic Systems Int Ltd
Centurion Laboratories Private Limited
Laboratoires Clarins
Anicare Pharmaceuticals Pvt Ltd.
Vipor Chemicals Private Ltd.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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6 comments: Post Yours! Read Comment Policy ▼

  1. How cleaning of same AHU is validated during the manufacturing of API in powder processing and packaging area to avoid cross contamination

    1. To avoid cross contamination, companies use separate AHUs for different processing areas. If you have same AHU for different areas then you must do risk assessment for the same.

  2. How the cleaning of single AHU is validated during powder processing and packing area during manufacturing of API (Non sterile) to avoid cross contamination. Can you suggest some SOP for this process

    1. You can validate this by taking swab sample from the equipment in the area that has shared AHU when processing was carried out in other area. The sampling area must be idle when processing was carried out in other area.
      It will validate that cross contamination doesn't occur in area with shared AHU when material is processed in other area.

    2. Ensure the cleaning of the equipment surface before keeping it idle to avoid contamination in cross contamination validation. 😊

  3. There is a small confusion in MACO calculation for intermediates. Can i consider MACO for Intermediates as 100ppm without calculation or do I have to derive the MACO by using any formula from APIC guidelines


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