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Introduction : Cleaning is necessary to avoid cross contamination from one product to another. Cleaning process

used for cleaning of equipments needs to be established to ensure that it is capable of consistently achieving desired level of cleanliness. To ensure the state of cleaning Hold time Study is required.

This validation study to be executed for Cleaned Equipment Hold Time study (CEHT) of drug manufacturing equipments.

This is intended to establish the acceptable duration for which cleaned equipment can be stored safely and allowed for next use.

After expiry of the established/validated hold time of cleaned equipment, a suitable cleaning shall be recommended.

This protocol is intended to validate the hold time of cleaned equipments used in the Manufacturing and Packing area for the manufacturing/holding packing of various products like Tablets and Capsules.

Protocol for Hold Time Study of Cleaned Equipment (CEHT)

OBJECTIVE :

• The objective of the cleaned equipment Hold time will provide the high degree of assurance and documented evidence.
• That the cleaned equipments can be hold for a definite period of time under the specified environmental condition and within this hold time,
• Before the expiry of established Hold time of cleaned equipments, the equipments are safe for manufacturing, holding of products.
• It is a process of providing documented evidence that the holding method employed for cleaned equipments.
• Consistently controls potential carryover of microbial contamination into subsequent product to a level which is below the predetermined level of acceptability.
• Successful completion of the study requirements shall provide assurance that the precaution taken for prevention of microbial contamination to the cleaned equipments shall consistently achieve desired level of cleanliness.
• The equipment shall consider suitable for use if the next product to manufacture shall not be contaminated.
• This acceptance level shall based on microbial load per gram of the oral dosage form and also on analytical capability to determine bio-burden.

SCOPE :

• This Hold time study protocol shall evaluate the acceptability of cleaning procedure and holding or storage of cleaned equipment (CEHT).
• As all the cleaning procedures of various equipment’s are in place and are in use.
• This hold time study protocol is exclusively prepared for establishing the cleaned equipment hold time.
• As the adequacy of cleaning procedure of various equipments for removal of potential chemical carryover of previous product to the next product is a separate study,
• Thus this study is mainly being carried out to evaluate the cleanliness of equipment on holding for a definite time period and after expiry of this time equipment shall not be used, with respect to bio burden or microbial growth.
• The protocol shall also define the responsibilities, procedure, acceptance criteria and conclusion for establishing the Cleaned Equipment Hold Time.
• The Cleaned Equipment Hold Time study shall perform on maximum and minimum capacity of equipment’s, (Bracketing Approach) used for manufacturing or holding of product(s).

RESPONSIBILITY 

• Quality Assurance:

  • Preparation, Review and Approval of Hold time study protocol for cleaned equipment.
  • Provide the training to concerned personnel involved in hold time study.
  • Withdrawal of samples as per the sampling plan defined in study protocol .
  • Review the Hold Time Study data, and
  • Provide the summary and final conclusion of the Hold Time Study of cleaned equipment (CEHT).

• Production Department:

  • Ensure implementation of protocol.
  • Assist Quality Assurance department in withdrawal of sample for hold time study, and
  • To review Hold Time Study protocol & report of cleaned equipment.
  • Providing Training to the operators regarding holding time and storage precaution of cleaned equipment.

• Quality Control Department:

  • To perform testing and analysis in support of the Hold Time activity.
  • Submission of compiled results to QA for review.
  • To review the Hold Time Protocol & report.

• Engineering Department:

  • To provide support through preventive maintenance and calibration of equipment and instruments, respectively.
  • Measurement and calculation for equipment contact surface area.
  • Reviewing of validation protocol.

APPROACH : Hold Time Study of Cleaned Equipment –

• The approach of cleaned equipment Hold time study requires establishing the parameters.
• Parameters, which are critical factors for contributing microbial contamination to equipment, thereby enabling them to set priorities, develop grouping philosophies and establish the adequacy of cleaned equipment storage condition.
• The approach assists in determining which processes, equipment and products represent the greatest concern and may help to establish the criticality of holding methods.
• This includes
  • Cleaning program criteria,
  • Equipment characteristics,
  • Quality attributes of equipment design,
  • Formulation / product attributes,
  • Analytical methodology and manufacturing / Area / Process attributes.
• All the factors in the approach directly affect the ability to maintain equipment with its usability w.r.t microbial contamination.

• Note:

  • Product prone for microbial contamination preferably considered for hold Time study as this poses high risk to product, environment as well equipment microbial load.  
  • Also the study will be executed on product which has no anti-microbial in nature.
  • Thus a monitoring product shall be the most appropriate representative of all type of products  & will simulate the actual manufacturing environment.

 PROCEDURE : Hold Time Study of Cleaned Equipment (CEHT)

• The manual cleaning methods has been adopted for cleaning the equipments used for manufacturing of various products.
• This study to be done exclusively for cleaned (After execution of complete cleaning) equipments.
• After completion of cleaning, cleanliness shall verify visually and ensure the equipments are dry before sampling.
• Perform the sampling as per sampling plan.
• After sampling, ensure that the equipment should not left with any such condition which may promote the growth of microorganism on the equipment.
• During the holding or storage of cleaned equipment, storage condition shall simulated as per routine practices.
• Remember, Document any deviation, Discrepancies observed during cleaning, storage, sampling or analysis.
• Investigation shall carried out for identification of root cause.
• Take the necessary corrective and preventive action.
• Ensure the training of  all concern prior execution of this protocol.
• A suitable conclusion shall be drawn based on the finding of the microbiological testing results.

• To execute the study,

• Adopt the bracketing approach for Equipment . So that the equipment having similar
  • Make,
  • Model &
  • Design
• Equipments are grouped into one category and from the set of these groups, minimum as well maximum capacity of each equipment shall be selected for the purpose of Cleaned Equipment hold time study.
• The degree of ease for cleaning & holding of minimum capacity equipment is different from the maximum capacity,
• Hence, by selecting the both extreme capacity,
• It is scientific as well logical that the out come of the cleaned equipment study results will reliable and acceptable.
• This approach can applicable for other set of equipments / utensils used in the manufacturing during different stages like Granulation, Compression, Coating & Packing.
• Thus to execute the cleaned equipment hold time study, an equipment details shall prepare for the smallest capacity & the largest capacity, used in the same manufacturing facility. Refer Annexure-1.

• CLEANING TYPES:

  • Type “A” cleaning procedure
    • This cleaning procedure to be followed during the batch change over of the same product and strength or ascending strength (Provided colour is same or previous product is white)
    • For Example – Alprazolam 0.5 mg tablet to be manufactured followed by Alprazolam 0.25 mg tablet.
  • Type “B” cleaning procedure
    • This the cleaning procedure to be followed during change over of product with
      • Different APIs,
      • Colour,
      • Descending strength of similar activities,
      • Post maintenance of product contact parts,
      • When the next product is not known,
      • After consecutive five Type A cleaning or seven days which ever is earlier,
      • Before starting the operation if any equipment is not used within seven days after type B cleaning ,
      • With in five days of Type A cleaning and after the plant shut down for more than 48 hrs.
      • When next product is not known.
      • After major equipment maintenance.
    • For Example: Mesalamine 400 mg tablets  to be manufactured followed by Lithium Carbonate 400 mg tablet.

 CLEANED EQUIPMENT HOLDING PROCEDURE.

• Clean all the equipments as per respective cleaning procedures.
• Ensure awareness regarding the critical cleaning steps and methodology before execution of this protocol.
• Potable water for cleaning and final rinsing with purified water as cleaning agent.
• Do not use surfactant for cleaning of any equipment.
• This indicates the moisture content inside the equipment of cleaned equipment is critical and this may help in proliferation of microorganism during hold time.
• Before holding the equipment for future usage. Ensure the dryness of equipment..
• Use compressed air for drying the cleaned equipment before use or storage.
• Use compressed air for most of the CIP type equipment and
• Dry small equipments like WIP type by air.
• Take the necessary precaution to avoid re-contamination during drying and or Transportation from wash area to the storage area.

• As bio burden can sourced from

  • Environmental or
  • Storage conditions like
    • Excessive temperature,
    • Humidity,
    • Air born viable particle due to material or man movements in the equipment storage area,
• Take adequate protection to ensure during holding to maintain the required cleanliness.
  • By covering,
  • Closing the inlet or outlet or probable opening of equipments etc).
  • During study, impact of regular intervention shall consider to simulate the actual storage condition for cleaned equipment like AHU shutdown during weekly-off day , man movement for routine cleaning and sanitization of area etc.

• CRITICAL SITES

  • Those locations in which a contaminant is in danger of affecting a single dose with a high level of contamination.
  • Critical sites often require special cleaning emphasis.
  • Decide the critical sites on basis of the following:
    • Difficult to clean
    • Inspection difficulty
    • Difficult to reach the surface

• CONTACT SURFACE:

  • Classify the equipment surface into two categories like
    • Product contact parts and
    • Product non contact parts.
  • This study of Hold time of cleaned equipment has focused on the contact surfaces only.
  • In practice, the requirement of this study may change with non-product contact surfaces where a chance of migration of contaminant is there to the product during actual process.
  • Such equipment parts shall consider and the acceptance criteria shall remain same as that of contact surface.

• EQUIPMENT GROUPING.

  • In order to provide sufficient confidence on the findings of this study,
    • Selection of equipment for execution of cleaned equipment hold time study is critical.
  • All the equipment having similar
    • Design,
    • Material of construction,
    • Surrounding condition and
    • Similar man & material movement
  • Considered for grouping the equipments.
  • Perform the separate hold time study of cleaned equipment having different design and surface area.
  • This study shall also conduct for the various kind utensils used for
    • Dispensing or transferring the material,
    • Sampling from one container to the other or one location to other like Scoops , IPC bin, silicon sleeves, gaskets etc.
    • A separate hold time study shall perform by the help of an independent protocol.
  • Note : While establishing the hold time for cleaned equipment, consider the following important parameters/ attributes 
    • Type of cleaning
    • Type of equipment and its condition (Open, Closed, partially opened & wrapped etc.)
    • Environmental condition (Temperature, %RH, Air changes, man & material movement, maintenance etc.)
    • Nature of Previous product (Starch paste kettle or products having antimicrobial action)
    • Sampling (Techniques, location, frequency etc)
    • Method of Analysis

ACCEPTANCE CRITERIA: Hold Time Study of Cleaned Equipment (CEHT)

• Two criteria are widely used in Pharmaceutical industry to determine / establish the acceptable levels for bio-burden for cleaned equipment Hold time study are as follows:

• VISUALLY CLEAN:

  • After execution of cleaning procedure, inspection shall carry out for cleanliness and dryness of the equipment.
  • No residue should visible on the cleaned equipment and equipment should dry.
  • After satisfactory inspection of visually cleaned and dry equipment, microbiological load determination shall  carry out by applying different techniques of sampling like (as per defined sampling plan).
    • Swabbing or
    • Rinsing etc.    

  • Visual Inspection Criteria:

    • Equipment should visually cleaned and dry. (Pale yellow to brownish or rust like observation on its contact parts should be absent during holding an equipment)
    • From the surface inspected distance of inspection should NMT 3 ft, .
    • Angle of observation should from 15 º to 90 º.
    • Define the Intensity of light for the respective area.
    • Inspection should carry out at least three personnel before sampling.
    • All personnel performing the inspection shall have good vision.

  • MAL ( Maximum Allowable Microbial Load):

    • Total Bacterial count: NMT 100cfu / Swab.
    • Total fungal Count: Should be Absent / Swab.

  • JUSTIFICATION OF ACCEPTANCE CRITERIA:

    • The Swabs are being collected from the equipment surface and are wetted & extracted in purified water.
    • This technique will transfer the biological load from the equipment surface to purified water (Medium) through the swab sticks.
    • The result of each swab should be less than 100 CFU/ swab i.e as good as Purified water Microbial limit.

• EQUIPMENT’S CONTACT SURFACE AREA:

  • Prepare a list of largest and smallest equipment used for manufacturing and packing for products.(Refer Annexure-1) . Including..
    • Area,
    • Equipment name,
    • Equipment ID. Number,
    • Title of SOP,
    • Cleaning SOPs Number.
  • Consider only those parts of equipment which are coming into direct contact with product as contact surface area for sampling.
  • Among two or more equipment having almost similar contact surface area,
    • Then the equipment having maximum area shall be considered for sampling.
  • Apply a conservative approach by selecting the larger equipment contact surface as normally cleaning difficulty increases with the size of equipment.
  • For Example: Blister Packing machine (Rotary) is selected for cleaning validation having marginally more area as compared to Strip Packing machine.
  • Consider the larger equipment in case of product manufactured in different equipments

• OVERALL ACCEPTANCE CRITERIA:

• Use the cleaned equipment within its established hold time and the method of storage during its holding of an cleaned equipment is considered to validated
• In case of
  • Physical determination: When the product contact surfaces found visually cleaned.
  • Microbiological determination:
    • When sample results found free (Absent) of pathogens, yeast & molds (Total fungal count) is Nil per swab and total Bacterial count is not more then established acceptance limit.

SAMPLING PROCEDURE:

• Swab Sampling:

  • Swab sampling does not cover the entire equipment surface area and
    • Therefore sites should chosen with care.
  • In general, the critical contact sites are having highest risk for contamination.
  • It is important that, as a minimum, the swab represents worst-case locations on the equipment and
  • That the result is then extrapolated to, account for the total product contact surface area.
  • This calculation makes it possible to mark worst-case determination of potential carryover into subsequent product.
  • The sampling location shall include all locations that are known as difficult to clean (Refer: Annexure 2).

  • After visual inspection, Carry out the swab sampling.

  • Wet the swab in the purified water.
  • Collect the swab samples from different location of equipment.
  • Swab using parallel 5 horizontal strokes and parallel 5 vertical strokes by rotating the side in the previously marked area of 5 x 5 cm² ensuring that the entire area is swabbed.
  • Wear the sterile hand gloves and take the necessary precaution during sampling to avoid microbial contamination to the samples for pseudo positive results.

                 Note: To match the total specified Swab surface area, Alter the dimension,

                                However the total swabbing surface should less than 25 cm².

• • Securely placed each sample after swabbing test tubes and submitted to QC for testing.
  • Direction of swab strokes horizontally and vertically. Refer below diagram. 

• JUSTIFICATION FOR SAMPLING LOCATION:DIAGRAM:

  • It may appropriate to establish more intensive sampling schedules for critical sites, set tighter acceptance criteria for critical sites and ensure that enough detail is included in cleaning procedures to provide for reproducible cleaning of critical sites.
  • Thus sampling location and number of sample from each equipment shall be determined by considering the following parameters
    • Total Contact surfaces
    • Which is difficult to reach (Contact Part)
    • Contact parts, which are difficult to visually inspect.
    • Contact parts, corners/contour, which may lead to build up of residual matter.
    • Smooth or irregular surface.
    • Contact parts, sampled by swab and likely to have contamination.

RE VALIDATION CRITERIA:

• • Conduct the re validation on
    • Any major modification in the equipment.
    • Any change in standard Operating Procedure of Cleaning.
    • Modification in the storage condition of cleaned equipment.
    • Any failure of acceptance criteria.

• EVALUATION OF RESULT:

• Evaluate the results obtained from each equipment for sampled surface area and compared with the established acceptance limits.
• Examine the equipment visually after cleaning to check the cleanliness.
• Based on the data obtained, Evaluate the procedures adopted to hold cleaned equipment is adequate enough to provide the confidence of its usability within the established time frame.
• In case of failure due to any reason, unrelated to the performance of the equipment cleaning procedure,
• Then consider the additional study for establishing the Hold time.
• The cleaning procedure / technique, storage condition, sampling techniques should critically monitored against the standard written procedure and cleaned equipment storage procedure,
• If required, Amend the Sampling techniques.
• Validated the amended cleaned equipment storage procedure.
• Re check the appropriateness of analytical method.

CONCLUSION:

• Establish the cleaned equipment hold time by reviewing the results obtained from the analysis of the samples,
• Applying the logical approach, Draw the best possible conclusion .
• In case any sample does not meet the hold time acceptance criteria,
• Then stratified sampling considered for establishing the hold time of the equipment.
• Conclusion Should clear and precise by stating the exert hold time of cleaned equipments used in manufacturing Area.

CHANGE CONTROL:

• In case of failure to meet the desired cleaned equipment hold time, Do the necessary changes by reviewing the
  • Cleaning procedure,
  • Methodology,
  • Sampling technique,
  • Storage condition and
  • Steps involved in the same in details.
• Do the necessary changes through the change control procedure and Validate the the revised procedure.

ABBREVIATIONS:

• CFU                : Colony forming units
• Cm                  : Centimeter
• MAL               : Maximum allowable microbial Load
• Mcg                 : Microgram
• MTP                : Microbiological Testing Procedure
• mg                   : Milligram
• NMT               : Not more than
• NLT                : Not less than

ANNEXURES:

• Equipment details (Annexure-1)
• Sampling Plan & Result (Annexure-2)
• Cleaned Equipment Hold Time Study Report (Annexure-3)

DEFINITIONS:

• VALIDATION:

  • Validation defined as the established documented evidence so that a process would give products consistently which will meets its predetermined specification and quality attributes.

• CLEANING VALIDATION:

  • It’s a established documented evidence which assure that the current cleaning process is adequate to remove the traces / residue of previous product to the extent of predefined acceptance limit so that the next product shall retain its safety, purity and efficacy.

• CHANGE CONTROL:

  • A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect the validated status of facilities, systems, equipment or processes.
  • The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state.

• RE-VALIDATION:

  • A repeat of the process validation to provide an assurance that changes in the process/equipment introduced in accordance with change control procedures do not adversely affect process characteristics and product quality.

• WORST CASE:

  • A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.

• CLEANED EQUIPMENT HOLD TIME:

  • The time from the end of the cleaning process until the beginning of the use of the cleaned equipment for manufacture of the next product (CEHT)

REFERENCES:

• 21 CFR Part 211.67 & 211.111
• PIC/S January 2002, Annexure-15, Page 123 (Cleaning Validation)
• TGA Guideline Annex 15 Qualification and validation, 16 August 2002 Page 109
• JAPAN, GMP Guideline for Drug Products, 12.8 (Cleaning Validation)
• ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS, Recommended for Adoption at Step 4 of the ICH Process on 10 November 2000 by the ICH Steering Committee, 12.7, (Cleaning Validation)
• D& C Act, 1940, Schedule-M, (Validation and Process Validation), Point no.26.1.
• FDA, “Guide to inspections of Validation of Cleaning Processes” Division of Investigations,, office of Regional Operations, Office of Regulatory Affairs, ( (July 1993)
• PDA Technical Report No. 29, “Points to consider for cleaning Validation” Bethesda, Maryland (1998)