2. PRESENTATION ON CLEANING VALIDATION

3. INDEX  INTRODUCTION SIGNIFICANCE SELECTION OF SAMPLING TECHNIQUES ESTIMATION OF ACCEPTANCE CRITERIA RE-VALIDATION CRITERIA

4. INTRODUCTION  Cleaning validation is the process of assuring that cleaning procedures effectively remove the residue from Manufacturing equipment / facilities below a predetermined level.  This is necessary to assure the quality of future products using the same equipments, to prevent Cross –Cleaning validation provides such assurance. For example, in the U.S., section 211.67 of part 21 of the Code of Federal Regulations(CFR) states that “Equipment and utensils shall be cleaned,maintained,and sanitized at appropriate intervals to prevent contamination that would alter the safety,identity, strength, quality or purity of the drug product beyond the official or other established requirement.” Section 21.182 of part 21 of the CFR identifies that cleaning procedures must be documented appropriately, and that a cleaning and use log should be established.

5.  Rinse method  Swab method  Rinse method Sampling from wide area is possible Sampling is possible from a position not accessible by hand.  Swab method Possible to recover dried residues and insoluble substances  SAMPLING TECHNIQUES  Two types of sampling methods

6.  Equipment Cleaning Method The equipment cleaning procedures involves any one of the following 3 types of cleaning Process based on the manufacturing situation(s).  Type A Vacuums & dry wiping  Type B Vacuum / washing with purified water.  Type C Washing with purified water and finally wiping with Isopropyl alcohol

7.  TYPE C CLEANING – WHEN TO PERFORM After every 3 batches After 6 days of continuous production of same Product Cleaned machine/Equipment is not used for a period over 30 days Break down / Repair / Preventive maintenance AND PRODUCT CHANGE OVER

8. Product Details  Cleaning sop/sop training  Acceptance Limit (MAR)  Acceptance Limit per swab  Selection of sampling techniques  Validation of analytical method and spike Recovery study  Sampling and analysis  Summary report and conclusion  Evolution and approval of results FLOW CHART OF CLEANING VALIDATION ACTIVITY

9.  Estimation OF maximum Allowable Residue (MAR)  Maximum Allowable Residue (MAR) for an combination of products changeover in the subsequent product will be calculated by considering the smallest batch size,smallest strength and maximum daily dose among all the products manufactured.  MAR = Smallest strength * Safety factor* Smallest batch size Maximum daily dose Smallest Strength 2.5mg Safety factor 0.001 Smallest batch Size100kg Maximum Daily Dose4000mg

10.  Estimation of Acceptance Limit for each equipment Acceptance limit for each equipment will be calculated to the respective equipment surface area.Subsequently the final allowable acceptance limit be calculated for sampled surface area of individual equipment. Acceptance Limit Max.Allowable Residue * Equipment surface area for equipment = -------------------------------------------------------------- Total surface area of all equipment Acceptance Limit for the Acceptance Limit x Swab Area 16 cm 2) sampled surface ----------------------------------------------------------- Equipment Surface Area

11.  CLEANING VALIDATION PROCEDURE  Equipments are cleaned as per respective cleaning SOPs during product changeover.  Swab samples are collected from the predefined locations of all the equipments as per the sampling procedure to estimate the residue content of the previous product.  OR Rinse sample are collected After the Final Rinse  The cleaning procedure is considered to be validated for the listed products when the results of three runs are below the acceptance limits.

12. WORST CASE CRITERIA : 1. SOLUBILITY 2. ACCEPTANCE LIMIT

13.  SLECTION OF SAMPLING METHOD  Swab sampling technique is selected for sampling. Most difficult to clean locations are selected for sampling.  SAMPLING PROCEDURE  Sampling procedure  Swab samples shall be taken after the final cleaning of the equipment.  0.45micron filter paper shall be used for swabbing.  The filter paper shall be soaked in water for injection.  The filter paper carefully applied to the swabbing site.  The filter paper rubbed many times with a glass rod.  The filter paper shall remain on the swabbing site for 1minute.  The filter paper shall be removed and placed in a labelled Petri dish.

14.  How cleaning analysis performed?  Currently, cleaning validation samples are measured by using 1. HPLC 2. Spectrophotometric 3. TOC

15. Analysis methods--- Advantages/Disadvantages MethodAdvantagesDisadvantages HPLC1.Highly specific 2.Moderate to high sensitivity 3.Quantitative 1.Long analysis time 2.Expensive SPectophotometric 1.Moderate to high specificity 2.High sensitivity 3.Use as screening method 1.Not quantitative TOC1.Broad-spectrum 2.Low level detection 3.On-line capability 4.Rapid sample turn around 5.Minimal sample preparation 6.Fast & easy measurement 1.Non-specific 2.Aqueous soluble samples only

16.  ACCEPTANCE CRITERIA 10 PPM CRITERIA OR IF THE RESULTS ARE LESS THAN 10 PPM THEN THAT VALUE WILL BE CONSIDERED

17.  RE-VALIDATION The cleaning process shall be re-validated when 1.New Equipment is introduced 2.New product is introduced 3.Cleaning Method / Procedure is changed.

18. CONCLUSION ONCE VALIDATION IS OVER SAMPLES WILL BE COLLECTED AFTER PERFORMING TYPE-C CLEANING FROM 10 th CONSECUTIVE BATCH IRRESPECTIVE OF PRODUCT

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