Equipment Cleaning for Drug Products www.gmpsop.com 1 Scope and - - PowerPoint PPT Presentation

Equipment Cleaning for Drug Products

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Scope and General Types of Cleaning

• Product Contact Equipment, both Major and

Minor,… shall be cleaned and shall include …:

– Changeover Cleaning;… – Interval Cleaning*…; or – Dedicated Equipment Cleaning

• Equipment Cleaning:

– Designed to prevent Cross Contamination

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Use of Cleaning Instructions

• Equipment Cleaning must be conducted following

written Instruction-Records that shall be Approved by the … Production and Quality before being issued.

• Equipment Cleaning Instruction-Records:

– Shall be written in a detailed stepwise format for Manual Cleaning Methods. – A defined sequential operation for Automated Cleaning systems. – Record the completion of each significant time dependent

• r time critical step.

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Cleaning Instructions (cont)

• Equipment Cleaning Instruction-Records … shall include, and

not be limited to…

– cleaning and sanitizing agents, including amount to be used; – concentration of cleaning and sanitizing agents; – quality of water or other solvents used; – requirements for equipment disassembly and re-assembly; – temperature and pressure parameters; – flow rates for wash solutions and rinses for automated systems; – start and end times of each step; – volume/weight of rinse; – number of rinses; – tools/utensils employed; – agitation, recirculation, and/or reflux; – draining and drying; – identification/inspection of Dead-Legs; – method for indicating equipment cleaning status; – verification of cleaning; – method for protecting clean equipment from contamination; and – maximum time intervals for between use and cleaning.

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Cleaning Instructions

• Are SOPs, cleaning logs, or checklists where critical

steps are signed and dated satisfactory?

– Yes, but DP (drug product) sites are moving to separate batch records.

• Are draft procedures ok?

– Signed, approved procedures are to be used in plant.

• Must temperature and pressure be measured for

manual cleaning?

– If a parameter is critical to assure consistency, it must be measured.

• Is volume or weight of rinse always required?

– Primarily for vessels, line rinses and final rinse checks. May use time and flow rate.

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Primary Cleaning Parameters

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Equipment Logs

• Equipment Cleaning, Use, and Maintenance Logs, …

shall be maintained for each major Equipment Item … Information … shall include:

– Documentation of cleaning, use, and maintenance; – Date; – Start and finish times of the activity; – Equipment use, including product name, as well as initial and final Lot or Batch Numbers, of a campaign; – Signature or initials of individual performing the work; and – Signature or initials of a second person verifying the work.

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Equipment Logs

• May be more than one equipment logbook (e.g.,

separate cleaning & use vs maintenance log books)

• Each activity to clearly have start and finish times and

dates (e.g., cleaning vs use)

• Second person verifies that work was performed and

recorded in logbook, not as dual witness of equipment inspection unless there are no other primary records

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Routine Verification of Equipment Cleaning

• Routine Verification of Manual Cleaning Processes for Major

Equipment Where 100 Percent Visual Inspection is NOT Possible shall include inspection to verify the equipment is visibly clean and ….RAL.

• Routine Verification of Automated Cleaning Processes for

Major Equipment shall include inspection to verify the equipment is visibly clean, where accessible.

• Routine Verification of Manual Cleaning Processes for Major

Equipment Where 100 Percent Visual Inspection is Possible shall include inspection to verify the equipment is visibly clean…

• Routine Verification of Cleaning Processes …for minor

equipment shall include inspection to verify the equipment is visibly clean.

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Verification-Equipment Cleaning Summary

• 100 % Inspection- Not Possible

– During Validation

• Visual
• RAL (Critical points)

– Routine

• Visual
• RAL (Unless automated)
• 100 % Inspection- Possible

– During Validation

• Visual
• RAL (Critical points)

– Routine

• Visual

* Note- if only test is visual, then detection limit must be known Applies to major and minor equipment.

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Routine Verification

• Do we need to have a RAL test (rinse or swab), after

validation, if we cannot entirely see and inspect the equipment (e.g. large tanks)?

– Yes, if procedure is manual and equipment is not 100% inspectable, then a quantitative RAL test is required after validation. – No, if automated cleaning, RALs not required routinely, only visual as practical.

Balance inspection techniques for 100% (e.g. use of mirrors or cameras) and amount of equipment disassembly for thorough

• inspections. Otherwise, quantitative testing of the non-visual

parts such as rinse checks are to be implemented.

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Manual Cleaning - Guidance

• Requires detailed cleaning procedure and good

training to be reproducible and effective

– More prone to higher variability and human errors than automated or semi-automated methods

• Unavoidable for certain equipment pieces

– Small glassware items – Valves – Other intricate parts

• Can be validated with 3 runs, but should be assessed

more frequently than automated methods.

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Major vs Minor Equipment

• Minor:

– scoops, thiefs, paddles, attachments to major equipment (e.g. chutes)

• Small and open to allow 100% inspection
• No moving parts
• Not a potential single point contamination (fill needle)
• Major:

– Metal detectors, Dedusters (moving parts) – Vessels and bins (large surface area) – Sieves and mills

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Visual Detection Limit

• If the Only Verification of Cleaning Processes

to be Conducted on a Piece of Equipment is Visual, then the visually detectable quantity must be known and documented.

• Visually Detectable Quantities shall be based
• n literature or on laboratory studies.

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Visual Detection Limit

• Quantify when visual is the only verification

method for routine verification

– No routine RAL – Meant for changeover cleanings

• The level of visual acceptance may differ for the type of

cleaning: changeover, interval or dedicated.

• Literature limits may be used (4 mcg/cm2 =

25mcg/in2)

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Visual Guidance

Laboratory studies typically include:

• The spiking of coupons of a known surface area that

represent the materials of construction present within the system.

• The coupons are spiked at the swab RAL concentration and

adjusted to be directly proportional to the size of the coupon.

• The coupons are dried and examined under conditions

designed to represent the actual manufacturing environment by trained analysts and designated as visible, or not visible, at the RAL.

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Visual Guidance (cont.)

• If literature references are used as the basis for determining the

likelihood of visual detection:

• Report any evidence that suggests the compound of interest is not

visible at the RAL.

• For instance, during validation if rinse and/or swab checks for

cleanliness fail test acceptance criteria, but the visual inspection noted no visible residues.

• The same can be true for the laboratory determined visual limit.
• If evidence from manufacturing contradicts the limit reported by the

laboratory the anomalies should be monitored carefully

• If deemed necessary, changes made to the lab conditions intended to

represent the actual manufacturing environment (e.g., light intensity, distance from the subject, use of representative tools).

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Visual Inspection- Lighting

• Lighting shall be sufficient to facilitate visual

inspection for residues.

– Question: What is sufficient? It depends. Extra lighting (e.g., flashlight) may be needed to see within a tank, where as room lighting is enough to inspect a hopper. Must be able to see residue.

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Double Checking

• An Individual other than the one who

performed the cleaning must verify that major equipment is visibly clean.

Comment: The equipment and associated documents must be inspected by a second individual. May be Production or QA

• colleague. Does not need to be immediate. It not meant as a

dual witness for individual steps.

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Cleaning Level and Frequency

• The Need for Cleaning, Type/Level of Cleaning, and

Cleaning Frequency Within a Campaign shall be defined and documented. Interval cleaning shall be performed as required during a campaign.

• Rationale for Interval Cleaning and cleaning steps

used shall be documented and shall be based on the product being manufactured.

API has expanded text on restoration to intended use, deleted “rationale”.

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Campaign Length - Dedicated Equipment

• Maximum Length of a Campaign Before Which

Dedicated Equipment Must Be Cleaned shall be determined and the adequacy of the cleaning procedures documented by considering, and not be limited to, the following:

– potential for microbial growth in the used equipment; – stability of product residues when exposed to environmental conditions; – accumulation of product and/or degradation residues in the equipment; – environmental conditions; and – ease of cleaning after a single versus multiple uses.

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Campaign Length- Dedicated Equipment

• Specific to “dedicated” since non-dedicated is validated.
• Least stable and most difficult to clean products are of most

concern

• Is stability profile known for formulation when exposed?
• May need to consider degradation product residuals on

equipment

• Interval clean-ups may occur within a campaign

Interval clean-ups are good practice for longer periods of use, preventing build-up of residues.

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Cleaning Materials- Detergents

• Approved Cleaning and Sanitizing Materials … shall

be compatible with the surfaces to be cleaned. These materials are Raw Materials* and shall be purchased, received, stored, and approved.

Question: Is check of the certificates of analysis enough? No, need an ID test as a minimum.

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Detergents - Guidance

• Formulated for Industrial Use, may contain several ingredients

– Acidic (citric, phosphoric acids) – Basic (KOH or NaOH) – Surfactants – Chelants – Dispersants (low- molecular polymers) – Gylcol ethers (water miscible solvents)

• Need to have method sensitive at acceptance criteria (e.g. pH,

Conductivity, TOC)

• Test for most difficult ingredient to remove.
• Usually concentration is 1 - 5%
• Wt % Limits are based upon 10ppm of the largest non-water

component

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Detergents - Guidance

• Useful in certain areas

– When solvents not permitted or to reduce solvent use. – Stains/spots

• Analysis during validation

– Nonspecific (pH, TOC, UV, Conductivity) or – Specific (HPLC, IC-Ion Chromatography) certain components

• Acceptance criteria

– ADI (Acceptable daily intake)- toxicity based calculation or – GMP default limit

• Include detergent in cleaning evaluation study, if warranted.
• Routine or periodic evaluation after validation.
• Vendor will evaluate removals; may have data on most-difficult to

remove or deleterious component.

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Cleaning Solutions

• Cleaning Solutions that are Prepared and Stored shall

…indicate at least the following..

– Signature or initials of person preparing the solution, – Concentration of solution at time of preparation, – Date and time of preparation, and – Reevaluation or Expiration Date for solution. Comment: Vendor could provide data or have stability (e.g use within 7 days). Type of water used is important.

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Dry Equipment

• Equipment, if Wet, shall be dried immediately after

cleaning.

• Equipment Drying shall be performed using one of

the following methods (note detail removed for API):

– Heat, – Filtered circulating air or gas, – Filtered forced air or gas, and/or – Vacuum. When it is not possible to dry the equipment immediately upon completion of cleaning, a timeframe for the drying step shall be established that is supported by microbiological data.

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Dry Equipment

• Is alcohol (70% IPA) spray and air drying as last step

acceptable? Yes.

• Is air drying alone sufficient?

– One of the methods in practice standard 120.8 may be better. – Evaporation of water-rinsed equipment is ok.

• Residual water must not remain in pockets of the equipment.
• Microbiological concern. Supportive data is needed.
• Use only when other methods not practical.
• Can alternate methods such as lint free wipes may be used?

– Yes, may need optional practice standard? Good practices: The last steps of the cleaning procedure address the drying

• f the equipment, using one of the approved methods. For air drying, the

equipment openness, air movement, and room conditions (% RH, temperature) are factors in determining the necessary requirements. Rinse just before use is another practice.

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Status

• For each major equipment unit, Cleanliness status shall be

indicated at the time the activity is performed…using labels …or electronic system…shall use the following status designations:

– Hold for cleaning – Being cleaned – Clean

• Status system includes…signature of who placed label, time

and date API provided relief on exact wording of designations.

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Storage

• Measures to protect clean equipment…for example

– Store Dry – Close tank openings – Close tablet machine covers – Cover open flanges – Protect portable equipment by sealing in protective bag or shrouding

• Cleaned Portable Equipment must be segregated from in-

use/dirty equipment.

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Time Limit ‘Dirty’ Equipment

• Maximum Allowable Time Intervals for Periods

Between Use and Cleaning shall be specified and shall include consideration of the effects of variables that could impact cleaning (e.g. temperature).

• Maximum Allowable Time Intervals Between Use

and Cleaning must be demonstrated in at least one cycle …documented during the validation exercise

APIs has specified that maximum time is 14 calendar days for housekeeping purposes. Good practice: DP sites typically clean within a day of use. Caution: Wet material that may dry or harden on standing may need more than one lot.

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Time Limit Clean Equipment Hold time

• Maximum Allowable Time Intervals for the Periods Between

Cleaning and Next Use shall be specified for equipment stored in conditions with environmental exposure. If the maximum allowable time intervals are exceeded, the equipment must be re-cleaned. For equipment stored under protected conditions, no maximum allowable time interval is required.

• Maximum Allowable Time Intervals Between the Completion
• f Cleaning and Reuse must be established and validated if the

equipment is not stored under protected conditions.

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Special Cleaning

• After completion of maintenance or instrument calibration that

required opening, an evaluation …to determine level of cleaning

• Prior to Use, New Equipment shall be cleaned. At a minimum,

the equipment shall be verified as visually clean.

• Use and Cleaning History must be determined for product

contact equipment that has been used by third parties or by another GMP facility … documented, and it must be verified that previous product residues were removed.

• Commercial Production Equipment, used to manufacture

clinical Batches/Lots, for which cleaning has not been previously validated per approved procedure, must be verified as clean by visual and residue testing after the clinical production

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Clinical Batches in Production Equipment

• The most stringent acceptance criteria must be used. Concern
• ver the marketed, commercial batches is of concern
• Analytical methods must be in place before commercial

equipment is used

• Detergents and microbiological considerations remain for the

equipment after the clinical batches.

• Consider effect on current limits (e.g., clinical batch becomes

smallest batch size). Good practices: Some sites have procedures for handling and evaluating new R&D compounds. Close cooperation with R&D and/or use separate dedicated equipment. Analytical methods transfer, criteria, cleaning methods, and/or arrangements to test samples are planned beforehand.

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Pre-Use Inspections

• Pre-Use Inspections shall be performed immediately prior to use

following a changeover cleaning and documented in the batch/campaign record of the next lot/batch to be processed in the product contact equipment. Pre-use inspection shall verify that the equipment: – has been cleaned; – is visibly clean; – all identification from the prior product has been removed; – the cleaning records are complete; – if applicable, analytical results are satisfactory; and – the maximum allowable time period between cleaning and next use was not exceeded.

• The Quality Team must approve all executed cleaning records.

Good practice: Pre-use inspections recorded in next batch record.

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Cleaning Failures

• Equipment Cleaning Failures During Routine

Monitoring (i.e., visual and/or analytical result failures) must be documented and Investigated according to established Site procedures.

• Failures during validation must be documented and

investigated,

Good practice: Ensure equipment is quarantined, pending results.

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Why Investigate failures?

• To understand cause of failure /determine root

cause

• To document actions taken arising from failure
• To help prevent future failures - RFT
• Corporate standards requires it
• FDA expects it

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API Cleaning Failure Investigations shall consider and not be limited to:

– Operator error; – Equipment malfunction; – Procedure deviation; – Sampling; – Impact of campaign length; – Impact of time limits; – Quality of cleaning solvents; – Trend analysis of historical cleaning failure rate for product and the equipment item group; and – Consideration of the next product batch size and the limit based on that batch size (versus worst case limit).

Equipment Cleaning Failures

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Common Areas for Improvement

• Adequate development and transfer of cleaning processes

– Chemistry, solubility, stability – Pilot/Lab trials before validation/production.

• Specific instructions- automated vs manual

– CIP preferred – Lower variability, reproducible – Detailed

• Equipment/procedural changes

– Need tight controls during validation and afterwards – Changeover cleaning (3x) is performed over long period (>1 yr) – Deadlegs/sample valves and other cleanable equipment design considerations

• Handling of Out-of-Spec (OOS) results

– Measurements taken when exceeding acceptance criteria – Have procedure for handling cleaning OOSs

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Solvents for Final Rinse

• Solvents Used for Final Rinsing including water shall

be at least as high quality as the solvents used for subsequent processing. Recovered solvents shall not be used for equipment cleaning.

Good practice: The final rinsing should be representative of the dosage form to be processed in the equipment, as a minimum. For example, Purified Water USP for oral solids dosage forms and WFI for sterile products.

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Stains

• Stains - in the event an equipment item is

stained …, an evaluation must be conducted … described, mapped or the location(s) identified and documented.

Good practice: Stain registers made available to individuals performing future visual cleaning verification. Not an excuse to delay maintenance.

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Training

• Personnel Responsible for Equipment Cleaning

Operations and Sampling must be trained and qualified in …. Training effectiveness shall be documented. – General operational task training – Swabbing training – Training on specific cleaning procedures.

Good practice: Provide cleaning overview training

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Product contact to be validated

• Equipment Changeover Cleaning Procedures must be

Validated for all Product Contact Equipment (both Major and Minor Equipment) used for multi-product Production… Cleaning measures used to perform Interval Cleaning and Dedicated Equipment Campaign Cleaning shall follow Approved procedures and shall include visual inspections for cleaning verification, but are not required to be validated.

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Why Validate Cleaning?

• ICH Q7a section 12.7 (APIs) states ‘Cleaning

processes should normally be validated’

• FDA Regulations and guidelines -‘Guide to

inspection of validation of cleaning processes’

• ‘Particular attention should be accorded to the

validation of …cleaning procedures’ (WHO)

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Evaluations

• An Evaluation of Equipment Cleaning Practices must be

conducted, documented, and approved by the validation team for each drug product. This evaluation may be a single report

• r several reports. The purpose of this documentation is to

justify the decisions made in developing the cleaning validation project plan. This evaluation will determine for each equipment unit:

– what material(s) are being removed - include consideration of at least the following items:

• In-Process materials;
• Active Pharmaceutical Ingredients (API);
• Drug product;
• Raw Materials;
• Foreign Matter;
• Cleaning and sanitizing agents;
• Solvents
• Microorganisms and endotoxin

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Evaluations (Cont.)

• This evaluation will determine for each equipment unit:

– what residues will be tested for; – what analytical test methods are to be used; – cleaning parameters and applicable ranges - concentrations, temperatures, times; – residue acceptability limits; – which sampling method(s) will be used; – potential for degradation by-products or conversion products; – suitability of the cleaning agent(s) for the materials of construction of the equipment; and – equipment surface finish (e.g., stainless steel, glass, polypropylene).

Comment: Evaluations are similar to “prestudies” done before validation.

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Equipment Design and CIP Features - Guidance

• Design or remove unclean connections, dead legs, nozzles,

lines, ball valves, etc.

• Clean-in-place (CIP)

– Optimize process parameters before validation – Sprayballs - complete coverage; – Recipes- templates and controls

• Minimize tank nozzles; maximize size of tank nozzle
• Piping

– Gaskets flush – Fluid Velocity- 1 m/sec - 2 m/sec, depending on extent of dead legs. – Pitch- drainage, 1/8”/ft

• Filters, pumps, heat exchangers- drainable

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Most difficult to clean

• Equipment Cleaning Validation …shall be based

upon the most difficult to clean product … Acceptability Limits (RAL) … minimum calculated RAL shall be used for all product combinations… in the Equipment Item or Unit.

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Most difficult to clean

• Where can the MDD (Max Daily Dose) and LD50 be

found?

• MDD - Prescribing information (e.g. PDR) should state the

normally prescribed dosing range. The upper or maximum is used.

• LD50 - for nonactives, detergents, etc. Material Safety Datasheet

(MSDS) , Safety Information Sheet (SIS), vendor, a toxicology database.

• MTD (TA) - Minimum therapeutic dose is usually smallest tablet,

capsule, or pediatric dosage for liquids and suspensions.

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Selection of most difficult product

• Selection of The Most Difficult To Clean Product/Process

requires consideration of at least the following:

– solubility of residues in water and solvents, including acids and alkalies; – adherence of residues to surfaces that must be cleaned; – whether cleaning is manual, automated, or semi-automated; – equipment surfaces; – equipment configuration and disassembly; – ease of detection of residues by visual inspection; – potential for Biofilms, polymers, or other side products to form during or prior to the cleaning operations; and – increased difficulty of cleaning over time after use.

Selection of the most difficult to clean product/process shall be documented in the validation project plan.

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Selection of most difficult product

• Can solubility alone be used as a criteria?
• No, solubility of the active may be a major criteria, but other

items should be considered, especially with dosage forms.

• Excipients may form the basis of difficulty of cleaning.
• Examples are certain polymers in a film-coating pan (e.g.,

methacrylate (Eurdragit)) , or granulation colorants in a drying apparatus.

• It may difficult to quantify, and as such there may be

more than one worst-case or difficult to clean compound.

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Microbial limits

Microbial Acceptability Limits for Equipment Cleaning shall be established and validated, when required.

Comments: Depends on nature of product. For Solid Oral doasge forms, microcount for water (before equipment contact and value in rinse) can be used for limits.

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Sampling methods

• Validated sampling methods must be used to determine

residue levels after cleaning. Swabbing is the primary method…Swabbing and rinse must be validated by recovery studies.

• Rinsate method – a measured volume of solvent shall

thoroughly wet all surfaces…

• Swabbing method - …shall be performed in locations from

which there is likelihood of transfer of residue

• Sampling method recovery levels of 50% or greater are

acceptable…used as a correction factor

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Validation Project plan

• A Cleaning Validation Project Plan must be approved by

Validation,… Production and ….Quality representatives of the Validation Committee. The Validation Master Plan shall include a list of systems requiring cleaning validation and the validation approach to be used.

Good Practice: Reference can be made to equipment or product status lists maintained separately. This information must be readily available and clearly show the status and plans of validation.

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Equipment Grouping

• Equipment with the Same Design and Operating

Principle shall be grouped for the purpose of

• validation. These groupings shall be documented and
• justified. Cleaning validation shall be performed

using three executions of the same cleaning procedure using any combination of equipment within a group. Grouping is a strategy that may be used, but items may also be validated individually, without grouping.

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Example of Grouping-Drug Products

Equipment Groups

• Water-soluble
• Water insoluble (detergent)
• Acid/base soluble
• Others (e.g. solvent for special

drug product equipment)

Common Procedures/Products

• Granulators-

High shear Low Shear

• Blenders

Rotational Ribbon/Blades

• Mills
• Dryers
• Tablet presses
• Film-coaters
• Encapsulation machines
• Liquid tanks

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Example of Matrixing-Drug Products

Equipment Group - Equivalency for cleaning (disassembly, wash, wipe down, detergent) Product Group - Capable of being cleaned with that SOP Validation

• Must include most difficult/worst case product within group
• Clean procedures are validated (SOP1, SOP2)
• Could be combination of products, ≥ 3 executions). Validation protocol for each procedure.

Equipment Group Clean Procedure Products Validation Runs Granulators SOP 1 (base, acid, water) A B 3 C SOP 2 (detergent, water) D E 3 Tablet Presses SOP 3 (water) D,E,G 3 Dryers SOP 4 (water) D,G 3 Coating Pans SOP 5 (detergent, water) D G 3

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Validation Protocol contents

• An Equipment Cleaning Validation Protocol … shall include
• r reference, …. at least the following …

– Approved Cleaning Procedure/Instruction-Records to be validated; – Products addressed by the protocol; – Description of equipment; – Campaign lengths, if applicable; – Residue materials to be removed; – Cleaning parameters to be evaluated; – Cleaning and sanitizing materials to be used; – Analytical Methods; – Microbiological test methods; – Sampling plans, including rationale for the selection of specific Sites identified for sampling; – Sampling methods; and – Approval page with approval signatures and date of final approval.

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RAL Limits

• Residue Acceptability Limits (RAL) for cleaned equipment shall be

established by Qualified personnel based on empirical data and an approved method of calculation. For all drug products, the Residue Acceptability Limit for Therapeutic Materials based on Therapeutic Dose (RALT) applies. For Non-Therapeutic Materials (e.g., cleaning and sanitizing agents), the Residue Acceptability Limit for Non-Therapeutic Materials based on Toxicity (RALN) applies. Special limits shall be established for those substances that are considered through medical or toxicological review to be toxic or

• cytotoxic. These special limits shall be justified on a case-by-case

basis.

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RAL Calculations Equipment Train

• Residue Acceptability Limits (RAL) must be

calculated using the sum of product contact surface areas of all common equipment items/units between product A and B. Where there are more than one Equipment Train configurations, the largest total surface area shall be used in the RAL calculation.

Compare: Equipment train is used in RAL for drug products (10 ppm) whereas equipment unit is used i n API (25 ppm).

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Analytical Methods

• Validated sampling methods must be used to determine

residues after cleaning, when required…validated by use

• f recovery studies.
• Analytical Methods Used for Validation must be

validated and have detection limits with sufficient sensitivity to detect the established acceptable level of residues

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Analytical Methods Validation Report

• System suitability results
• Linearity/reproducibility around swab and

rinse limit

• Recovery study results
• Recovery factor, if necessary
• Suitability of method utilised

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Validation – 3 lots

Validation consists of three consecutive, successful executions …using one or more of the following

• ptions:
• …at the end of a regularly scheduled campaign; and/or
• …at campaign lengths less than the maximum campaign

length, ….at least one trial is at full campaign length. ….using the next most difficult to clean product, may be conducted prior to completion of the three validation trials of the most difficult to clean product.

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Criteria of Cleanliness

• Criteria for Equipment Cleaning Validation for

both major and minor equipment shall be as follows:

– Visibly Clean; and – Removal of residue (i.e., therapeutic and/or non- therapeutic material) to predetermined acceptance criteria.

• In addition, the RAL for minor equipment

items shall not exceed the maximum RAL for the process equipment items or equipment unit.

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Validation Reports

• Validation Reports shall discuss the results from the

execution of the protocol and shall be approved by the

• SVC. A Final Report shall be issued following three

successful executions of a cleaning procedure. Interim Reports are required if consecutive cleaning validation trials are more than three months apart.

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New Products

• Cleaning Procedures for New Products must

be validated by three consecutive successful executions of the cleaning procedure.

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New Non-therapeutic Material

• A New Non-Therapeutic Material (e.g.,

cleaning agent) used in product contact equipment must be evaluated by the SVC and an assessment report(s) issued that addresses the probable impact of the new material on the current equipment cleaning validation plan.

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Changes

• All Planned and Unplanned Changes

– established change control and/or investigation procedures – SVC must approve the impact analysis – Determination if Revalidation or further actions are required. – Include changes:

• Production process,
• Cleaning methods,
• Cleaning materials,
• Sampling methods,
• Analytical methods,
• Microbiological methods,
• Configuration of equipment or equipment assembly,
• Number of Lots/Batches in a campaign, and
• Maximum time interval between use and cleaning.

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Periodic Review

• Periodic Review of Cleaning Procedures relative to

all equipment units shall be performed at least every two years. …include review of:

– change control documents – cleaning procedure deviations – cleaning result investigations.

An assessment of the validated state of the cleaning procedure for the equipment shall be written into the conclusion of the report.

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• Must Calculate:

– Maximum Allowable Residue, MAR (Carryover),

• Therapeutic Data/ Toxicity Data (LD50)

– Maximum Residue Acceptance Limit, RAL

• Rinse Limit, ppm or mg of A /Kg rinse check solvent
• Swab limit, ug/cm2 or ug/swab
• Issue with current equations in Appendix I, II on next product

B and use of 10 ppm. One proposal is presented. There is more than one way (e.g. varying cap limit) to arrive at same proposed RAL result. Units must agree, i.e. MARs should have proper units when comparing to 10 ppm (mg active A/ kg next product B).

Calculations

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Calculations -

Product being cleaned is Therapeutically Active.

% active

1, 2. Calculate MART, MARForm

MTD - product being cleaned MDD – next product Safety Factor

• 3. Compare to GMP default limit of 10ppm
• 4. Calculate RALT

Rinsate

• 4. Calculate RALT

Swab

Weight of Rinsate Next Product Batch Size Surface Area of Equipment Next Product Batch Size

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Calculations- Therapeutic (step 1)

1. Determine Maximum Allowable Residue as mg of A per kg

• f B (both activity):

TA (mg of A) · conversion (106 mg of B/kg of B) · (SF = 0.001) MAR T = BB (units) · CB (mg of B/unit)

• TA - Minimum Therapeutic Daily dose of A (e.g. ATC - 10 mg/day)
• BB x CB - Maximum Therapeutic Daily dose (e.g. SILD 3 x 50 mg or 150 mg/day).
• MART Units of this are mg active A per kg of active B
• Example- MART = 10 mg ATC x (106 mg active SILD/kg of active SILD) x 0.001

150 mg active SILD MART = 66.7 mg active ATC/kg of active SILD

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Calculations - Therapeutic (step 2)

Note: Need to convert this to: mg A per kg of next product B, since MART is active A allowed only into the active of B, not the active A allowed into the next product B. The next product B or “Formulation B” is what would be contaminated with active A. The MAR of mg A/kg of next product B is the maximum carry-over concentration providing 1/1000 of a dose of A into next product B.

• 2. Determine Maximum Allowable Carry-Over Concentration

mg of A per kg of next Product B:

MARForm = MART (kg active A/kg active B) x kg active B/kg formulation B

• Example- (11% of the formulation in the equipment is active SILD)

MARForm = 66.7 mg active ATC/kg of active SILD x 0.11 kg active SILD/kg form SILD

MARForm = 7.3 mg active ATC/kg of formulation SILD

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Calculations –Therapeutic (step 3)

3. Compare this MAR carry-over to 10 ppm (10 mg A per kg of next product B). Use the lowest in the RALT limit equation.

• Example of ATC and SILD:

The MAR of 7.3 ppm (mg ATC/kg Form SILD) would be used as it is lower than 10 ppm.

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Calculations - Therapeutic (step 4)

4. Determine the RALT for the rinse and/or swab, using the smallest next product B batch size.

MARForm(mg of A/kg form B ) · LB(next product smallest batch size) RAL T = Rinse weight (kg ) or Equipment train surface area (cm2) – The smallest product batch size in equipment, LB, not only active B amount. – Units kg formulation B cancel and RAL is in mg of A/kg rinse or area (cm2)

• Example of ATC and SILD:

7.3 mg ATC/kg Form SILD x (500 Kg Form SILD ) RAL T = 320,000 cm2 RAL T = 11.4 µg ATC/cm2 Note: Swab recovery must be incorporated into the limit calculation or reporting of results.

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% active

2, Calculate MARN, MARPORM

• 3. Compare to GMP default limit of 10ppm

Surface Area of Equipment Next Product Batch Size Weight of Rinsate Next Product Batch Si

• 4. Calculate RALN Rinsate
• 4. Calculate RALN Swab

ADI - product being cleaned MDD – next product

LD50

1a) Calculate NOEL

Safety Factor

Calculations – Product being cleaned is Not Therapeutically Active.

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Calculations – Non-therapeutic (step 1)

• 1. Determine MARN using:

NOEL (mg of N/day · conversion (106 mg of B/kg of B) · (SF = 0.01) MARN = BB (units) · CB (mg of B/unit)

• 1a) NOEL - acute oral LD50 x SF (0.0005/day) x 70 kg (human weight)
• 1b) ADI = NOEL x 0.01 (Acceptable Daily Intake- part of MAR equation)
• BB x CB - Maximum Therapeutic Daily dose (e.g. SILD 3 x 50 mg or 150 mg/day)
• MAR Units of this are mg nonactive A per kg of active B
• Example- CIP 100 detergent removal and SILD next product

1a) NOEL = 860 mg/kg x 0.0005/day x 70 kg = 30.1 mg CIP 200/day 30.1 (mg of CIP100/day · (106 mg active SILD/kg active SILD) · 0.01 MARN = 150 mg MARN = 2007 mg CIP100/kg active SILD

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Calculations – Non-therapeutic (step 2)

• 2. Determine Maximum Allowable Carry-Over Concentration

mg of A per kg of next Product B:

MARForm = MARN(kg active A/kg active B) x kg active B/kg formulation B

• Example- (11% of the formulation in the equipment is active SILD)

MARForm = 2007 mg CIP100/kg of active SILD x 0.11 kg active SILD/kg form SILD

MARForm = 221 mg nonactive CIP100/kg of formulation SILD

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Calculations –Non-therapeutic (step 3)

3. Compare this MAR carry-over to 10 ppm (10 mg A per kg of next product B). Use the lowest in the RALN limit equation.

• Example of CIP100 and SILD:

The MAR of 10 ppm (mg CIP100/kg Form SILD) would be used as it is lower than 221 ppm.

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Calculations- Non-therapeutic (step 4)

4. Determine the RAL N for the rinse and/or swab, using the smallest next product B batch size.

MARForm(mg of A/kg form B ) · LB(next product smallest batch size) RAL T = Rinse weight (kg ) or Equipment surface area (cm2) – The smallest product batch size in equipment, LB, not only active B amount. – Units kg formulation B cancel and RAL is in mg of A/kg rinse or area (cm2)

• Example of CIP100 and SILD:

10mg CIP100/kg Form SILD x (500 Kg Form SILD ) RAL T = 1000 Kg (or 1000 L of DIW) RAL T = 5.0 ppm (mg CIP100/Kg of DIW rinse)

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Safety Factors

• RALT = 1/1000
• RALN = 1/100

Note: NOEL calculation includes body weight of 70kg vs 50kg.

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Worst Case limits

• By equipment, building, product, or site.

– Equipment, Building or Site- all As to all Bs in that specific item, area

• r site. Conservative, but may be impractical.
• One RAL for each equipment, building or site

– Product Groups or Product- product A to all potential Bs. Practical.

• One RAL for each product .
• Limits affected by

– Low MTD to high Max Daily Dose (next product)

• Low MARs, below 10 ppm

– Small batch size of next product

• Low RALs

– Large rinse weight or large equipment surface area

• Low RALs

– Toxicity

• If very low, may need limitations on product scheduling or dedication.
• May be able to concentrate rinse samples or swab larger areas.

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Comparison APIs vs Drug Products

• Scope

– API must account for Intermediates

• Methods of cleaning

– API- more automated, repetitive cycles, various organic solvents are used. – DP – more 100% inspection possible

• Non actives-

– DP plant - excipients – API plant- starting materials, acids, bases, reagents, solvents

• Testing of residues

– DP - Both use but swab more prevalent and applicable than rinse. – API- Both use but rinse is more applicable than swabs.

• Limits

– Cap (wt % or default) is 25 ppm (APIs) and 10 ppm (DP) – APIs use limits per equipment item, whereas DP use per equipment train

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Case Study- Solid Oral Dosage Form

• Cleaning SOP developed for each equipment item
• Acceptance criteria justified:

– 11.1 µg/cm2 active ingredient and – 13.3 µg/cm2 for detergent, for equipment swab surfaces

• Major equipment- granulator, dryers, mill, bins, tablet

press, ancillary (metal detector, deduster), coating pan, were swabbed. Visual inspection also.

• Three executions per SOP on representative equivalent

equipment items; (e.g 3 bins of 25 bins), 3 of 4 granulators, 3 of 5 tablet presses, 3 of 5 coating pans,etc.)

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Case Study (cont’d)

• SOPs were specific; WIP (Wash-in-Place) recipes were

finalized.

• CIP-100, 1.0%, potassium hydroxide, detergent is used.
• Swab results were acceptable for 3 runs/procedure

– Active- < LOQ and some 2 µg/cm2 – Detergent- < LOQ and one value 8 µg/cm2

• Hold times Qualification - performed once.
• Equipment logs are used to record execution of cleaning

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Case Study (cont’d)

Visual inspection of major/minor equipment Swabbing-Major Equipment- Granulator, Fluid-

Bed dryer, Mill, Bins, Tablet Press (with metal detectors, dedusters) and Film-coating pans.

Rinse - not performed

• Equipment grouped- equivalent, same cleaning

procedure (e.g. 6 “equivalent” tablet presses)

• Product contact major equipment evaluated for

Active and Detergent residues

– Active- HPLC – Detergent- Ion Chromatography

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• Non-active contact (granulation and coating suspension

tanks) - evaluated for detergent only.

• Process characterization study done before validation to

demonstrate success and confidence in methods.

– Detergent concentration – Swab locations determined – Finalize cleaning SOP

• Equipment holding times (both clean and dirty)

determined.

– Dirty- 10 days, longest time in 3 validation runs. – Clean- 14-40 days depending on items- Microbial test – Criteria- (LT 5 Colony Forming Units/25 cm2)

Case Study (cont’d)

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Principal Cleaning Deficiencies US FDA Inspection Reports

• Cleaning validation is lacking or incomplete
• Solvents, materials or parameters used are not specified
• Description or detection limits of the analytical method are missing
• Cleaning acceptance criteria are not defined
• No standard cleaning methods in place
• Detergents used are not researched
• No visual inspection is carried out
• Technique of swabbing for difficult-to-clean parts is not used
• Sampling methods are not used; No adequate sampling plans
• Recovery factors are not calculated in the analytical method
• Concern over allergenics, penicillins, cephalosporins, potent steroids

& cyctotoxics (dedicated facilities/equipment, acceptance limits).

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