Cleaning Validation Protocol

CLEANING VALIDATION

1. Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing of pharmaceutical products.

2. Pharmaceutical products can be contaminated by other pharmaceutical products. The objective of cleaning validation is the confirmation of a reliable cleaning procedure so that contamination is reduced to predetermined levels.

3. Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts.

4. Cleaning procedures for product formulation changeover should be validated.

5. Generally in case of batch-to-batch production of the same product, it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined as appropriate.

6. Cleaning procedures for products and processes which are very similar do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation program which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the “worst case” can then be carried out which takes account of the relevant criteria. This practice is termed "Bracketing".

7. Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. Control of change to validated cleaning procedures is required. “Testing until clean” is unacceptable.

8. Operators carrying out manual cleaning procedures should be adequately supervised Dedicated equipment may be necessary for products which are difficult to remove, for equipment which is difficult to clean, or for products with a high safety risk.

9. The existence of conditions favorable to microorganisms and the time of storage should be considered. The period and, when appropriate, the conditions of storage of equipment before and after cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.

10. Samples should be taken according to the cleaning validation protocol. The choice of sampling methods should be demonstrated to provide accurate information about the effectiveness of the cleaning process.

11. Two methods of sampling considered to be acceptable are direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods may be desirable in circumstances where accessibility of equipment can mitigate against direct surface sampling.

12. The suitability of the material to be used for sampling and of the sampling medium should be determined to assure predetermined levels of recovery.

13. Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant and the appropriate volume of the samples. A direct or indirect measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.

14. Other techniques which may be used include coupon sampling, solvent sampling, product sampling, placebo sampling and direct surface monitoring.

15. If cleaning agents are used, acceptable limits should be defined for residue of the agent after cleaning.

16. Analytical methods should be validated.

17. Analytical methods used to detect residuals or contaminants should be appropriate for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable.

18. The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery.

19. The rationale for selecting limits for product residues should be based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable.

20. One cannot ensure that the contaminant will be uniformly distributed throughout the system. It is also invalid to assume that a residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch.

21. In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical variations (active decomposition materials) may be more difficult to remove.

Cleaning Validation Protocol

CLEANING VALIDATION 1. Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing of pharmaceutical products. 2. Pharmaceutical products can be contaminated by other pharmaceutical products. The objective of cleaning validation is the confirmation of a reliable cleaning procedure so that contamination is reduced to predetermined levels. 3. Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts. 4. Cleaning procedures for product formulation changeover should be validated. 5. Generally in case of batch-to-batch production of the same product, it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined as appropriate. 6. Cleaning procedures for products and processes which are very similar do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation program which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the “worst case” can then be carried out which takes account of the relevant criteria. This practice is termed "Bracketing". 7. Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. Control of change to validated cleaning procedures is required. “Testing until clean” is unacceptable. 8. Operators carrying out manual cleaning procedures should be adequately supervised Dedicated equipment may be necessary for products which are difficult to remove, for equipment which is difficult to clean, or for products with a high safety risk. 9. The existence of conditions favorable to microorganisms and the time of storage should be considered. The period and, when appropriate, the conditions of storage of equipment before and after cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation. 10. Samples should be taken according to the cleaning validation protocol. The choice of sampling methods should be demonstrated to provide accurate information about the effectiveness of the cleaning process. 11. Two methods of sampling considered to be acceptable are direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods may be desirable in circumstances where accessibility of equipment can mitigate against direct surface sampling. 12. The suitability of the material to be used for sampling and of the sampling medium should be determined to assure predetermined levels of recovery. 13. Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant and the appropriate volume of the samples. A direct or indirect measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process. 14. Other techniques which may be used include coupon sampling, solvent sampling, product sampling, placebo sampling and direct surface monitoring. 15. If cleaning agents are used, acceptable limits should be defined for residue of the agent after cleaning. 16. Analytical methods should be validated. 17. Analytical methods used to detect residuals or contaminants should be appropriate for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable. 18. The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. 19. The rationale for selecting limits for product residues should be based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable. 20. One cannot ensure that the contaminant will be uniformly distributed throughout the system. It is also invalid to assume that a residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch. 21. In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical variations (active decomposition materials) may be more difficult to remove.

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CLEANING VALIDATION PROTOCOL

1.0 APPROVAL SHEET
Approval Sheet contains particulars about the Names of persons with designations and signature with date and nature of work performed for preparing this document. User of this document should prepare the Table and incorporate in this section.

2.0 Introduction:

Medicinal products can be contaminated by other medicinal products, by cleaning agents, by microorganisms or by other material (e.g. Air borne particles, dust, lubricants, raw materials, intermediates, auxiliaries. In many cases, the same equipment may be used for processing different products. To avoid contamination of medicinal products, adequate and validated cleaning procedures are essential.

3.0 Unit Operation:
Cleaning of Equipment.
4.0 Objective:
To ensure that the Cleaning Procedure as detailed in the SOP is effective and removes all residues up to a predetermined acceptance level, and that there is no possibility of any resultant cross contamination.
5.0 Site of the Study :
Production Department.
6.0 Validation Team:
Representatives from : Production
Quality Assurance
Quality Control
Engineering
Individuals name to be entered in the report.

7.0 Description of the Equipment to be cleaned:

All equipment’s used in the manufacturing of Tablet and Capsule: Details of the machine like
Machine name and Code No. of Equipment/s to be entered in the report.
8.0 Standard Operating Procedure (SOP) for Cleaning of Equipment:
SOP applicable to the cleaning of equipment: SOP No. To be recorded in the report.
9.0 Control:
9.1 Absence of traces of Active Ingredient and cleaning agent in swab/Rinse by validated analytical method.
9.2 Determination of bioburden (Microbiological Contamination)
9.3 Analytical method validation for cleaning validation shall be done. It should include analytical performance parameters like limit of detection and recovery of swab samples.
9.4 SOP for taking swab: SOP No. to be entered in the report.
10.0 Experimental Details:
10.1 Clean the equipment as per the SOP.
10.2 Collect the Swab / Rinse individually various parts as per the sampling plan.
10.3 Collect the final rinse in potable water.
10.4 Collect final rinse in purified water.
10.5 Swab various parts of the equipment for microbiological analysis.
10.6 Estimate the content of active in Swab / Rinse as per the validated analytical method.
10.7 Find the presence of cleaning agent in all rinse.
10.8 Visual inspection of final rinse.
10.9 Visually inspect the equipment and its parts to ensure that it is clean.
0.10 Based on the above analysis, calculate the amount of residue present in each rinse and swab and estimate probable contamination in the next product.
10.11 Calculate the limits for Acceptance criteria as follows:
10.10.1 DOSE CRITERION
FORMULA:

I/J x K/L x M = _________mg of previous product / 4sqinch.

Where,
I = 0.001 of smallest strength of previous product in mg / tablet (or) Capsule.
K = No. of dosage units per batch of final mixture of next product.
J = Maximum number of dosage units of next product taken / day.
L = Surface area of equipment's common for both the products.
M = 4 square inch / swab.
10.10.2 10 PPM CRITERION:

FORMULA:

R x S x U
_______________ =________mg of previous product / 4sqinch
T
Where,
R = 10
S = Kilograms per batch of final product of next product.
T = Surface area of equipment's common for both the products.
U = 4 square inch/swab.
The carry over of previous product residue should not be more than the lowest value
among the dose criterion & 10 ppm criterion.
10.11 Criteria for microbiological contamination:
10.11.1 Total Bacterial Count: Not More Than (NMT) 100 CFU per 4 square inch / swab
10.11.2 Mold and Yeast: NMT 10 CFU 4 square inch / swab
11.0 Acceptance criteria:
11.1 Equipment should be visually clean.
11.2 Residue of previous product or products in the swabs should be less than the minimum
Value determined by dose Criterion and 10 ppm Criterion.
12.0 Type of validation: Concurrent Validation
13.0 Frequency : Three validations exercise per equipment.
Three validations exercise per equipment for change in cleaning procedure.
Three validations exercise per equipment for major change in equipment.
Re – validation every two years.