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Slide 1 Presented By Kedar Waykul Basics of cleaning validation Slide 2 Objective Of Cleaning Validation Slide 3 Objective Of Cleaning Validation Objective of Cleaning Validation : To Avoid the Contamination of subsequent manufactured product by the previously manufactured product. To design the cleaning procedure in such a way that, the process will reduce the contamination up to the predetermined acceptance criteria To have a documentary evidence that the approved cleaning procedure available will provide the Clean equipment To confirm a reliable procedure so that the analytical monitoring may be omitted or reduced to a minimum in the routine practice. Slide 4 Contaminants What are the contaminants: 1. Precursors to the Active Pharmaceutical Ingredient 2. By-products and/or degradation products of the Active Pharmaceutical Ingredient 3. The previous product 4. Solvents and other materials employed during the manufacturing process. 5. Micro-organisms This is particularly the case where microbial growth may be sustained by the product. 6. Cleaning agents themselves and lubricants Slide 5 CLEANING VALIDATION APPROACHES Two Approaches by which we can perform the cleaning validation: A)Equipment based cleaning validation Validating the cleaning procedure with the product which is worst on the particular equipment. B)Product based cleaning validation Validating the cleaning procedure with the worst case product by considering the common equipment train Slide 6 WORST CASE Worst case determination: Following are the Criteria's to be considering during worst case determination: Solubility :Less soluble product ,more worst the situation Potency: More potent product ,more worst the situation Toxicity: More toxic product ,more worst the situation Batch size of Next Product: Lowest batch size ,more worst the situation Strength: Lowest strength of previous product ,more worst the situation Maximum daily dose of nest product: Highest the number of daily dose ,more worst the situation Common equipment surface area: Largest common surface area of equipment, more worst the situation Slide 7

FACTORS AFFECTS CLEANING PROCEDURE Four Factors to be consider during effectiveness of cleaning procedure and can be assessed during validation study: Time: The longer a cleaning solution remains in contact with the equipment surface, the greater the amount of product that is removed. An increase in time leads to a reduction in the chemical concentration Temperature: product are affected to varying degrees by temperature. In the presence of a cleaning solution. Most products become more readily soluble as the temperature is increased. Selection Cleaning agent : Drug concentrations vary depending upon the Chemical agent, type nature and concentration of cleaning agent. Mechanical Force: Mechanical force can be simple hand scrubbing with a brush or as complex as turbulent flow and pressure inside a pipeline. Mechanical force aids in product removal and typically reduces time, temperature, and concentration requirements. Slide 8 CLEANING METHODS Methods of cleaning Foam: Foam is produced through the introduction of air into a detergent solution as it is sprayed onto the surface to be cleaned. Foam cleaning will increase the contact time of the chemical solutions, allowing for improved cleaning with less mechanical force and temperature. High Pressure: High pressure cleaning is used to increase the mechanical force, aiding in product removal. In high pressure cleaning chemical detergents are often used along with increased temperature to make product removal more effective. Slide 9 CLEANING METHODS Clean in Place (CIP): CIP cleaning is utilized to clean interior surfaces of tanks and pipelines of equipments. A chemical solution is circulated through a circuit of tanks and or lines then returned to a central reservoir allowing for reuse of the chemical solution. Time, temperature, and mechanical force are manipulated to achieve maximum cleaning. Clean Out Of Place (COP): COP cleaning is utilized to clean tear down parts of fillers and parts of other equipment which require disassembly for proper cleaning. Parts removed for cleaning are placed in a suitable container and cleaned Using chemical solution and agitation. Mechanical: Mechanical cleaning normally involves the use of a brush either by hand or a machine such as a floor scrubber. Mechanical cleaning uses friction for product removal. Slide 10 ACCEPTANCE CRITERIA DETERMINATION Visually Clean Criteria Visual Inspection: Visually clean means that the surfaces have no visible residues when viewed under appropriate lighting. The use of visual inspection as a criterion for equipment cleanliness has always been a component of cleaning validation programs. Mendenhall proposed the use of only visual examination to determine equipment cleanliness as long ago as 1989 (1). He concluded that visible cleanliness criteria were more rigid than quantitative calculations and clearly adequate. The US Food and Drug Administration limited the use of visually clean criterion between lots of the same product (2). LeBlanc raised the question of whether a visible limit as the sole acceptance criterion could be justified (3). Author(s): Richard J. Forsyth , Julia Roberts , Tara Lukievics , Vincent Van Nostrand Many research teams have established quantitative VRL levels. Fourman and Mullen determined a visible limit of ~100 g per 2 X 2-in. swab area (8) or

~4 g/cm2 . Jenkins and Vanderwielen observed residues as low as 1.0 g/cm2 with a light source (9). Forsyth et al. determined <0.4- to >10- g/cm2 VRLs for active pharmaceutical ingredients (APIs) and excipients (6). Slide 11 ACCEPTANCE CRITERIA DETERMINATION Chemical Content determination: Slide 12 ACCEPTANCE CRITERIA DETERMINATION Chemical Content determination: A)Dose criterion (0.001) (I/J) X (K/L) X U Where I = (SF * Smallest strength of product A manufactured)/day expressed as mg/day & based on the number of mg of active ingredient J = Maximum number of dosage units of Product B1 taken/day K = Number of dosage units per batch of final mixture of Product B1 L = Equipment surface area in common between Product A & B1/B2 expressed as cm² U = Swab area Slide 13 ACCEPTANCE CRITERIA DETERMINATION Chemical Content determination: 10 PPM Criteria: R X (N/L) X U Where R = 10 mg active ingredient in product A/kg Product B2N = Number of kgs per batch of final mixture of Product B2 L = Equipment surface area in common between Product A & B1/B2 expressed as cm² U = Swab area Slide 14 ACCEPTANCE CRITERIA DETERMINATION Toxic Effects Toxicological Criterion : MACO=NOEL x K x U SF x J x L NOEL=LD 50x 70 Kg X E Where NOEL = No observed Effect Level LD50 = Lethal Dose 50 in mg/kg animal for active ingredient in product A J = Maximum number of dosage units of Product B1 taken/day K = Number of dosage units per batch of final mixture of Product B1 L = Equipment surface area in common between Product A & B1/B2 expressed as cm² U = Swab area E = Empirical Constant = 2000 SF = Safety Factor = 0.01 - 0.001 Slide 15 ACCEPTANCE CRITERIA DETERMINATION Microbial Contamination Microbiological Contamination Limit The cleaning validation techniques for microorganisms include Swab method, Surface Rinse method, RODAC Plate method, Limulus Amoebocyte Lysate method, Bioluminescence method Slide 16 CLEANING AGENT Cleaning Agent: Selection criteria's for Cleaning agent selection: Soluble, non Toxic, non reactive with equipments, easy to remove, effective for removal of dirt from the equipment parts. Determination of Cleaning agent acceptance criteria: Cleaning agent safety

based limits are typically calculated from a safety factor of an acceptable daily intake (ADI), a (1/1000 or more) reduction of an LD50 preferably by the same route of administration, or reproductive hazard levels. If the calculated limit is found to be higher than a less than 10 ppm carryover to the next batch, then the limit can be set to the more stringent 10 ppm carryover level for the safety based limit. Calculated safety based limit in mg/cm2 or mg/ml of cleaning Agent: Limit (mg/cm2 or L) = ADI carryover - see below (mg) X Smallest Next Batch (kg) Size of Shared Equipment (cm2 or L) X Biggest Daily Dose or of Next Batch (kg) ADI carryover (mg) = LD50 by administration route (mg/kg) Xbody weight (kg) X (1/ 10,000 or 1/1000*) 10 ppm carryover: Limit (mg/cm2) = 10 mg residue on just cleaned surface X Next Batch Size(kg or L) 1 kg of L of next product X Size (cm2 or L) shared equipment * conversion factor used to convert LD50 to acceptable daily intake, use higher number for low LD50s Slide 17 Grouping and Bracketing Grouping and Bracketing: To simplify cleaning validation, similar equipment may be grouped into equipment families. These families are based on equipment design, construction material, geometry, complexity, functionality, or cleaning procedure. Grouping may involve separately validating the extremes of a group (for example, the largest and smallest portable tanks in a group), or it may involve testing only the worst case in a group (for example, the most difficult to clean transfer line Cleaning following the manufacture of products may be validated for individual products or may be validated by product group. Grouping by products includes considerations of potency, toxicity, and cleaning difficulty. Products in groups must be manufactured using the same equipment categories and cleaned by the same or similar cleaning processes. Chemical and physical properties of ingredients (including excipients) must be considered when grouping by products; excipients may be more difficult to clean Slide 18 SHEET FOR ACCEPTANCE CRITERIA CALCULATION Slide 19 SHEET FOR ACCEPTANCE CRITERIA CALCULATION Slide 20 SAMPLING TECHNIQUES Sampling Techniques: Rinse Method ( Indirect sampling) Rinse Sampling ,This is in effect a special case of swabbing. Either a pressure spray is used to rinse a vessel and the liquid draining out collected and analyzed or, more usually, a sample of the final rinse from the CIP sequence is collected. However for the test to be of any value it is essential that the rinse fluid makes good contact with the surfaces being examined. Additionally the liquor used for the final rinse must be of defined characteristics. Final rinse samples can, of course, be assessed for the presence of product, chemical contamination or microbes but in all cases the contaminant materials must be either soluble or physically removed by the rinse if they are to be detected.

Slide 21 SAMPLING TECHNIQUES This method is not as direct as swabbing but will cover the entire surface area (and parts inaccessible to swabs) It is important to ensure chosen solvent has appropriate recovery for residues being quantified This method allows much greater ease of sampling than swabbing Slide 22 SAMPLING TECHNIQUES Swab Method ( Direct sampling) This technique, involving rubbing a swab over a surface in order to pickup any contaminants, can be used for both chemical and microbiological analyses. When performing a swab analysis it is extremely important that a defined area is monitored . Care must also be taken when deciding which parts of the plant to swab; monitoring only easily accessible areas can lead to optimistic results whereas the examination of poorly accessible areas alone can give pessimistic results. Again the person carrying out the collection of the swabs needs to use their eyes. If the swab becomes visibly dirty whilst the sample is being taken, inadequate cleaning is immediately Indicated. Slide 23 SAMPLING TECHNIQUES Swab sampling does not cover the entire equipment surface area therefore sites must be chosen with care. It is important that, as a minimum, swab sites represent worst case locations on the equipment and that the result is then extrapolated to account for the total product contact surface area. Due to the nature of this method which employs physical forces as well as chemical forces it may be necessary to perform sampling technique evaluation. Swabbing efficiency (% recovery) for the swabbing method must be determined. Using this technique it is possible to sample insoluble residues due to the physical action associated it. Slide 24 SAMPLING TECHNIQUES Stability of Swab or rinse: Before completion of analysis the active should be stable. So stability of swab or rinse sample should be determined and the analysis should be conducted within the predetermined stability period of rinse and swab sample. Slide 25 TRAINING REQUIREMENTS TRAINING Training regarding approved processes or protocols used for cleaning validation studies such as cleaning processes and sampling processes, is performed and documented by approved training policies or procedures. Personnel who collect samples for cleaning validation and who perform visual inspections must be trained before these collections and inspections. Operators are routinely retrained for validated manual cleaning procedures, particularly when there has been a change in any validated cleaning procedure. Slide 26

ANALYTICAL METHOD Validated Analytical Method The method used to detect product residue or contaminants collected by swabs/recovery solvents should have following characteristic, Accuracy Precision LOD LOQ Specificity/Selectivity Linearity Ruggedness/Robustness Slide 27 RECOVERY STUDIES Recovery study: The swab recovery must be validated to determine the amount of analyte that can be recovered from a surface. Previous to validating the equipment cleaning procedure, the types of equipment surfaces for product manufacturing should be identified. This means if four types of surfaces are identified such as glass, stainless steel, Teflon, or rubber; each of the four surfaces must be tested for swab recovery. The study can be performed on simulated product contact surfaces. The efficiency of the swabbing procedure should be challenged at the acceptance criteria level for active ingredient, excipients, and detergent. Known amounts of active ingredient, excipients, and detergent will be added to each type of surface. The surface is air-dried and swabbed. The nature of the swab extraction is dictated by the analytical method, which has taken into consideration its dissolution properties as well as the analytical technique used. The amount recovered by the swab is determined using a validated trace level analytical method. Recovery from the surface is calculated as follows: % recovery from surface =Amount recovered from Swab (mg)x 100/Amount added to the surface (mg). A recovery factor of 70% is usually acceptable; but factors as low 50% may be obtained. In cases where low results are obtained in a reproducible manner, the sample surface area may be sampled again using a second swab, with the results obtained from both swabs added together. Slide 28 PERIODIC REVIEW Periodic review and revalidation are methods by which the performance of a validated cleaning process is evaluated to ensure that a state of control is maintained. At Genentech, a risk-based approach is used for setting periodic review and revalidation frequencies. The rationale for the revalidation frequencies should be appropriately documented and justified. Slide 29 PROTOCOL DETAILS Cleaning Validation protocol : DEVELOP A CLEANING VALIDATION PROTOCOL FOR THE PRODUCT AND THE EQUIPMENT BEING CLEANED Following details can be incorporate in the protocol (But not limited), 1. Introduction 2. Scope 3. Equipment 4. Cleaning procedure 5. Sampling procedures 6. Analytical testing procedure 7. Acceptance/Cleaning limits. 8. Acceptance criteria for the validation. Slide 30 ERRORS Common Errors 1. Failing to perform a good process flow, beginning with the raw material sampling process and focusing on obviously important stages such as the compounding or filling process. 2. Failing to train operators well, and failure to instill a sense of high commitment: Most common mistakes, such as not following procedures, not taking samples at

the time specified, improper handling of samples, not reporting discrepancies observed during the specific process executed, etc., undermine high quality performance and contribute to poor results. It is highly recommended to have representation from the validation department present throughout all runs. 3. Missing or inaccurate documentation: In addition, to the common errors noted above in #2, a lack of documentation also causes difficult situations during future audits, because important key information will be missing during investigations. This is often the basis for general misunderstanding of data. 4. Lack of good coordination and communication between the different areas involved in the validation process: Examples of poor coordination and communication include samples not being taken on time, required materials not being available, disputes within departments, lack of cooperation, and bad working environments based on placing blame rather than on cooperation. Slide 31 ERRORS Common Errors 5. Failing to understand the criticality of the sampling process: It is very important to take the samples at the time(s) established and for the proper durations (stability), taking correct quantities and volumes, attending to the proper handling and storage of samples, using the correct equipment, and other special considerations for samples requiring microbiological testing. 6. Failure to properly train persons in charge of sampling: This can have a major impact on the accuracy of microbiological sampling. 7. Not having an effective change control program: Once the validation process is completed, internal procedures impacted by the validation outcomes must be revised accordingly. It is frequently observed that the communication and follow up systems fail at some point and impacted procedures and activities are not modified. 8. Failure of manufacturing areas to consider the validation department in internal changes and procedure approval: Due to lack of technical knowledge in the validation area personnel in manufacturing might overlook or be unaware of important aspects that have impact from a validation point of review. 9. Failure of plant personnel primarily focused on the manufacturing operation, to require compliance with the cleaning validation procedures. Slide 32 ULTIMATE AIM Our ultimate Aim is to provide Best Quality Product to Customers Slide 33 THANK YOU

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