Cleaning Validation
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Transcript of Cleaning Validation
Unit 1
Cleaning Validation Validation and Verification
of Cleaning Processes
Trainer: Chandramouli R
Rationale...
● The basic reason for having good, effective, consistent cleaning procedures is to prevent the contamination of products made subsequently in the same equipment.
MECHANISMS OF CONTAMINATION
● CrossContamination with Active Ingredients● Microbiological Contamination● Contamination by Cleaning or Sanitizing Agents● Contamination by Miscellaneous Other
Materials
Type of facility vs. degree of risk of crosscontamination
Changeovers for API Facilities● Switch from batch to batch for same product (campaign situation)
● Switch from final step of one product to final step of different product
● Switch from final step of one product to intermediate step of a different product
● Switch from final step of one product to initial step of a different product
● Switch from intermediate step of one product to final step of another product
● Switch from intermediate step of one product to intermediate step of another product
● Switch from intermediate step of one product to initial step of another product
Changeovers for API Facilities...
● Switch from initial step of one product to the intermediate step of another product
● Switch from initial step of one product to the final step of another product
● Switch from initial step of one product to the initial step of another product
Dosage Form Changeovers
● Changeover from one batch of a product to another batch of the same product
● Changeover from one product to a different product
● Changeover from one strength of a product to a different strength of the same product
● Changeover from a product given by one route of administration (oral, topical, ophthalmic, etc.) to a product given by a different route of administration
ORGANIZING CLEANING VALIDATION
● riskbased rationales included in cleaning validation programs
● strong policies required to help drive the decision making
● How? Master Validation Plan for Cleaning
Master Plan
● Provide an overview of the site/facility/area that is governed by the Master Plan
● Provide an overview of the typical manufacturing process(es) that are to be performed in the area and the dosage forms that are produced
● Provide an overview of the types of cleaning that are to be used (e.g., automated CleanInPlace or Clean OutofPlace, semiautomated cleaning or manual cleaning)
MPCLV
● Provide the responsibilities of the various departments having a role in cleaning validation activities
● Provide the minimum requirements for the cleaning validation program, including:
– Necessary scientific rationales in support of the program:
● Residue selection● Equipment characterization● Product contact surface area calculation● Limits calculation● Sample site selection● Product grouping (if any)● Equipment grouping (if any)
Support programs for CLV
● Required studies in support of the program:– Analytical methods validation– Sampling method recover studies– Cycle development for cleaning processes
● Essential Programs that maintain the validated state and their required elements:
– Cleaning and testing, if any, to be conducted upon the introduction of new or repaired equipment
– Monitoring of cleaning after validation completion
Support for CLV
● Routinely conducted compliance initiatives on site that maintain quality and will affect the company’s ability to maintain the validated state
– Failure investigation– Change control– Preventive maintenance– Calibration– Revalidation
SOPs for CV
● Important SOPs Governing Cleaning and Cleaning Validation
– Development of cleaning SOPs (especially for manual cleaning operations)
– Equipment cleaning and use logs– Visual inspection requirements for cleaned
equipment– Equipment quarantine and release– Equipment sampling procedures for cleaning
assessments (e.g., swab, rinse, etc.)
Cleaning validation process flow
Validation vs. Verification● documented evidence to
ensure that cleaning procedures are consistently removing residues to predetermined levels of acceptability, taking into consideration such elements as batch size, dosing, toxicology, equipment size, and the like. A cleaning validation is typically completed by the accomplishment of a minimum of three consecutive successful trials. successful trials.
● documented evidence to ensure that cleaning procedures remove residues to a predetermined level of acceptability based upon the minimum of a single trial. Is performed to assure that the cleaning procedures used adequately clean the equipment when the manufacturing process or the cleaning procedures may be subject to change, and therefore cannot be immediately subjected to validation
Campaign manufacturing
● Campaign production is the manufacture of lots of the same product in a consecutive fashion such that:
– (i) no cleaning is performed between batches (typical of API manufacture, for example),
– (ii) sufficient cleaning is performed to ensure mechanical functionality of the equipment but equipment does not reach a visibly clean level (also common in API manufacture),
– (iii) cleaning is conducted to a visibly clean level with limited to no disassembly of the equipment (common to oral solid dose manufacture),
– (iv) full cleaning is conducted of product contact surfaces, but cleaning environmental surfaces and changeout of product associated disposable parts (e.g., gaskets, hoses) is not performed until end of campaign (common to high potency products and/or products associated with more stringent dosage forms).
Residue Identification
● API(s)
● Constituents of the cleaning agent
● Preservatives
● Precursors or starting materials
● Intermediates
● Processing aids
● Media
● Buffer
● Cellular debris or metabolites
● Particulate
● Bioburden
● Endotoxin
● Viral particles
● TSE
● Excipients
● Colorants, dyes, flavors or fragrances
● And many more!
Residue...
● those residues that are pertinent to dosage form or process
● those residues that are the most active/toxic and therefore represent the most risk to the next patient
● those residues that would damage the quality, purity, efficacy, appearance of the next batch produced
● those residues that would damage the next process (e.g., water in a hydrophobic process)
● those residues that are the hardest to remove (difficult to clean
Major Sampling Techniques and Their Attributes
Typical Cleaning Validation Assay Methods
Determination
● Commonly cited limits in literature and in regulatory guidance documents
● the surface of the equipment must meet the requirements of being:
– Visibly clean
– Not more than 1/1000th of a therapeutic dose in the next batch, or
– Not more than 10 ppm in the next batch, whichever ofthe latter two limits is lower.
– Worldwide regulatory guidelines indicate that manufacturers must define their own limits for cleaning validation.
Equation 1: 1/1000th of a Therapeutic Dose Approach
Equation 2: Typical Units for the 1/1000th of a Therapeutic
Dose Approach
Equation 3: SafetyBased Limit Approach for API Starting
Materials and Intermediates
Equation 4: Fraction of an Interfering/Enhancing
Substance Approach for in Vitro Diagnostics
Equation 5: Not More Than 10 ppm in the Next Batch
Equation 6: Typical Units for 10 ppm Limit
Interpreting CLV results...
● The equation for the limit and the equation for the result are on either side of a comparator.
● Limit > Result● Based upon equations (1), (3), (4), and (5), the
terms for the result
Equation 7: Terms for the Result
Equation 8: Typical Units for the Result
Equation 9: Setting mG limits
Equation 10 Setting per sample limits