OBJECTIVE

Main objective of the cleaning in drug manufacture is to remove residues of the justmanufactured product, so that those residues are not transferred to the subsequently manufactured product.

PHILOSOPHY

REGULATORY REQUIREMENT Cleaning validation. Cleaning procedures. Sampling plans. Analytical methods and limits. Cleaning agents.

Ref: 21 CFR PART 211 SEC: 211.67

LIMIT / ACCEPTANCE CRITERIA

Practical Achievable verifiable and Scientifically sound.

DETERMINING ACCEPTABLE LEVELS The acceptance levels are based on : Pharmacological dosage combined with safety factor. Toxicity of the residue. Analytical limit of detection. The process capability of the cleaning process.

TYPES OF CLEANING Types of cleanings during API manufacturing: Batch to Batch cleaning. Periodical thorough cleaning. Product to product change cleaning. Batch to Batch cleaning: When no solvents are used, take the powder and check for purity to ensure no degraded product is there. ( NOTE: Periodical cleaning to be finalized based on criteria given below.) When solvents are used, check for final rinse ( Volume for rinsing to be constant) Before the next batch is taken for purity by HPLC to confirm no degradation is taken place.

The limit needs to be Established based on trend data of three batches and after this monitoring is to be done for three batches to prove the validity. =Check for visual cleanliness on routine basis.

Periodical thorough Cleaning: To fix number of batches for the Periodical, conduct the study by collecting the samples from the equipment.

Collect the samples from the equipment for every 5 batches, 10 batches, 15 batches, 20 batches, 25 batches etc.,

Check the samples for any degradents by HPLC / Color / Description etc.,

Fix the number of batches in a campaign and give proper justification based on the analytical data.

After fixing the number of batches in a campaign, establish Equipment cleaning procedure and validate the cleaning procedure .

Based on the data of the three batches fix the limit.

Product to Product change over cleaning: Establishing Acceptance criteria: The acceptance criteria for maximum allowable carryover of one product to another product can be derived as follows. A. Based on Therapeutic Dose combined with a safety factor. B. Calculation based on 0.1% limit.gf`

A. Based on Therapeutic Dose combined with a safety factor: Use the following equation to calculate the maximum allowable carryover Dmin x BS MAC = -------------------- x SF _________ (1) Dmax Here: MAC : Maximum Allowable Carryover. Dmin : Minimum daily dose of Just manufactured product. BS : Batch Size of subsequent product. SF : Safety Factor . Dmax : Maximum Daily Dose of Subsequent product .

B. Calculation based on 0.1% limit: Maximum allowed in the next product . 0.1 = _________________________ x Batch size of next product. 100 Compare MAC value obtained by A & B choose whichever is lower value.When more than two products are manufacturing in the same facility, in that group, whichever is having lowest MAC clean the equipment upto achieve that lowest MAC limit and consider this lowest MAC limit as worst case limit. Based on mode of dosage form, use following Safety factors: 1/100 for topical products. 1/1000 for oral dosage products.

 1/10000 for injections, Ophthalmic solutions etc., For research and investigational drugs fix the limit 10 PPM for the product change over. Note: If the therapeutic or toxicity data is not available fix the blanket limit as 10PPM for product change over.

SELECTION OF CLEANING AGENT: High solubility of product to be remove. It should not degrade the product. It should be compatible with the equipment. It should not cause environment hazardous. It should not be a contaminant of subsequent product. Solvent must be feasible to the process and easily available. Hazardous solvents (Benzene, Ethylene Dichloride etc., ) should not be selected as cleaning agent.

Equipment Cleaning Procedure : Establish equipment cleaning procedure as per following steps. First Step ( Removing gross accumulations): Remove the gross accumulations of the just manufactured product. Disassemble the equipment as per Equipment disassemble procedure. Clean the all disassembled parts as per procedure and assemble all spare parts. Second Step (Washing of the Equipment): Wash the equipment with sufficient quantity of the cleaning agent. Reflux / Boil with cleaning agent if necessary. Sequential use of both dilute alkali and acidic medium if necessary. Perform actual washing of all product contact surface areas in this step. Third Step ( Initial rinses): Rinse the entire equipment surface area thoroughly ( Product Contact) ( ex: Inner top of the reactor, piping etc., ) with the fixed volume of the cleaning agent. Send the sample to QC / AR&D for analysis.

Fourth Step ( Second rinse / Final rinse): Rinse the entire equipment surface area thoroughly ( Product Contact) ( ex: Inner top of the reactor, piping etc., ) with the fixed volume of the cleaning agent. Send the sample to QC / AR&D for analysis.

Repeat Forth step if the results are obtained more than acceptable limits.

NOTE: Mention the detailed step wise cleaning procedure in equipment cleaning validation protocol

Sampling techniques: The following sampling techniques can be used for collecting the samples form the equipment Rinse sampling. Swab Sampling.

Rinse sampling: Use rinse sampling technique for large vessels, hoses etc., (reactors, pumps, big equipment etc.,) Rinse the entire equipment surface area with fixed quantity of the cleaning agent. Take cleaned and dried sample bottle and collect the sample from the equipment.

Swab sampling : 1. Use swab sampling technique, where ever swabbing of equipment surface area is accessible. 2. After unloading final rinse from the equipment, collect the swab sample from selected critical areas ( wherever possibility of more residue). 3. Take sufficient fixed quantity of disorbent to collect the swab sample. 4. Disorbent used for swab sampling shall be the cleaning agent in final rinse. 5. Take swab sampler and collect the swab sample from the equipment surface area and dip in to the disorbent. 6. Swab all the critical sampling points and collect the sample in a Cleaned sample bottle and send for analysis.

Selection of swab sampler: 1. Swab shall be compatible with the product. 2. Swab should not cause degradation of product. 3. It should allow extraction of the compound for analysis. 4. Swab should not release fibers. Fixing limits for sample: Limit in rinse sample: MAC x RF x 1000 S = ------------------------------- ____________________ (02) V Here: S = Allowable Limit in Rinse Sample in PPM. MAC = Maximum Allowable Carryover ( From equation no.01). RF = Recovery Factor. V = Volume of solvent used for final rinse for all equipment.

Limit in Swab analysis : MAC x RF x 1000 x SA S = -------------------------------- _________ (3) TSA x DV S = Allowable limit in Swab sample MAC = Maximum Allowable Carryover (Derived in equation no.01) RF = Recovery Factor 1000 = Conversion Factor in to PPM SA = Swabbed area for individual equipment. TSA = Total shared surface area of non-dedicated Equipment. DV = Disorbent volume.

Recovery factor(Rf): Validate the recovery of the extraction process by spiking the analyte at known concentration to determine the recovery. Recommended recovery is 80% , less than 80% is needs justification. Piece of the equipment use to study Recovery factor is similar Material of construction of Equipment used for the process. ADVANTAGES of SWAB SAMPLING Physically removes sample Adaptable to wide variety of surfaces. Economical and widely available.

DISADVANTAGES of SWAB SAMPLING An invasive technique that may introduce fibres. Results are technique dependent. Swab material and design may inhibit recovery of the method. Difficult to sample complex, large vessels, pipes, valves etc..)

ADVANTAGES of RINSE SAMPLING Easy to sample Allows sampling of a large surface area and porous area.

DISADVANTAGES of RINSE SAMPLING Residues may not be distributed homogeneously. Inability to detect location of residues. Rinse volume is critical to ensure interpretation of results. Residue may not be soluble or may be physically occluded in the equipment. Cleaning of a dirty pot particularly with dried out residue the rinse water to see that it is clean.

RINSE vs SWAB

Rinse sample is easy to sample, how ever Rinse volume is critical to ensure interpretation of results. Consumes more quantity of solvent.

Where as Swab sample is difficult to sample, but it Physically removes the sample from the surface and also Economical and widely available.

SUMMARY OF CLEANING VALIDATION I . WHAT IS TO BE REMOVED? Active ingredients . Decomposition of products of active ingredients. Microbiological contamination Particulate Sanitizing agents Lubricants

II. WHAT SAMPLING METHODS ARE BEING USED ? Swab sampling Rinse sampling Coupon sampling Placebo sampling