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Introduction: The cleaning validation Master Plan will function as an umbrella guidance document for all the cleaning validation protocols, programs, and procedures adopted to ensure that all the equipment utilized for the manufacturing of tablets and hard gelatin capsules dosage form is cleaned up at an acceptable level.

The Pharmaceuticals manufacturing entities engaged in the manufacturing of the following dosage forms:

• • Tablets (Uncoated and coated)
  • Capsules ( Hard gelatin)

This Cleaning Validation Master Plan is designed to demonstrate the approach of pharmaceutical manufacturing plants for cleaning validation to meet the current National and International regulatory guidelines.

 

• • In which the plant cleaning procedures are manual for each piece of equipment.
  • The cleaning validation Master plan is designed to provide guidelines for planning, execution, and successful completion of the cleaning validation program.

1.0     SCOPE OF CLEANING VALIDATION

• • This cleaning validation Master Plan is applicable to the solid oral dosage form, Tablets, and Capsules, manufactured.

• • On the introduction of new equipment/products, it will evaluate the guideline provided in the cleaning validation Protocol for demonstrating that the established cleaning procedure is effective for the new product/equipment also.

Also read: SOP for Product Recall

2.0     RESPONSIBILITIES

• • The Quality Assurance department shall be responsible for:

  • Preparation, Execution, review, and approval of the Cleaning Validation Protocol.

• • Coordinating with manufacturing for the collection of the samples as specified in the protocol.

• • Ensuring that the equipment is cleaned to the levels specified in the respective protocol.

• • Preparation, review, and approval of the Cleaning Validation Report.

• • Imparting training to personnel involved in cleaning validation.

  • The quality Control department will be responsible for:

  • Reviewing the Cleaning Validation Protocol and Report.

• • Development of the validated analytical method of sufficient sensitivity as mentioned in the Cleaning Validation Protocol.

• • Analyzing the samples withdrawn during the execution of the validation protocol.

  • The manufacturing department will be responsible for:

  • Reviewing the Cleaning Validation Protocol and Report.

• • Provide training to the manufacturing personnel for cleaning of equipment.

• • Executing the Cleaning Validation Programme.

Also read: SOP for Change Control Management

• • The engineering department will be responsible for:

  • To provide the surface area of the product contact parts of the equipment.

3.0      STRATEGY (VALIDATION APPROACH)

• PRODUCT BRACKETING

  • Due to the complexity of the manufacturing of multiple product use of the same equipment, a bracketing approach shall be applied for cleaning validation based on scientific rationale.

• • Insoluble/Practically insoluble and most potent with the highest concentration of active pharmaceutical ingredient drug product (In case the product is manufactured with different strength) shall select for the cleaning validation purpose for each equipment train.

• • Subdivide the product based on the flow of manufacture on the specific train.

• • In this approach, cleaning validation shall perform based upon the worst-case product selected for the highest equipment train to demonstrate a high degree of assurance of cleaning to prevent contamination that would alter the safety, identity, strength, purity, and/ or quality of the drug product to meet established specification.

Click to read: SOP for Vendor Management

• • An individual worst case shall identify from each equipment’s train (Based on the solubility in water and potency).

• • Identified Worst case may or may not be the same for each equipment train.

• • Select the products based upon manufacturing performed in either of the trains on the following criteria.
    • Active pharmaceutical Ingredient solubility in water (Insoluble in water).

• • • Most potent drug product and difficult to clean.

  • If two or more products are

  • Identical based on the above two criteria, then the product which occupies most of the train’s equipment. Select for cleaning validation.

• • Identify based on the above three criteria, then select colored products as the worst product.

• • Identified based on above all criteria and API and excipients use are the same as two or more products can be selected for validation.

• • If the selected product is very slow-moving and no plan for manufacturing then taking the next worst product, cleaning validation shall be performed.

Click to read: SOP for Document Management System

• • If the most potent drug product identified has 2 active ingredients (the combination of drug product) Select the product API having the lowest solubility (Insoluble in water) for cleaning validation.

• • Based upon the evaluation of the above criteria product matrix shall be developed and the ‘worst case’ product will be used for the cleaning validation program. where Cleaning Validation shall be conducted for 3 batches.

• • MACO shall be calculated from each equipment’s train based upon the product.

  • Cleaning Validation shall be executed for worst-case identified from each equipment’s train and the value of the results shall be compared with the MACO value from that particular equipment train.

• • If the new product enters the product matrix, the impact analysis on each equipment train shall be carried out based on solubility and potency criteria as per the new product evaluation form.

• • Change in cleaning agent and cleaning procedure shall require re-validation.

Click to read – Process Validation SOP and Protocol

• • If the equipment for tablets and capsules is not dedicated then the drug product shall be considered in each equipment train matrix in which it is manufactured.

• • If a drug product is manufactured in more than two equipment trains then it should be included in both the matrix for MACO calculation.

• EQUIPMENT BRACKETING

  • Equipment across the plant shall be subcategorized into equipment trains.

• • Identical, interchangeable pieces of equipment with the same cleaning procedure are grouped together.

• • Equipment with the same operating principle and same cleaning procedure, but with different surface areas, are grouped.

Click to read: Technology Transfer of Drug Product (SOP)

• • The equipment with the largest capacity and surface area will be considered for the calculation.

  • For equipment with different capacities but with similar design and operating principles and where cleaning procedures are equivalent cleaning validation can be performed in any one size of the equipment.

  • Change in equipment that does not fit into the established equipment train will require re-validation.

• • If the equipment of a particular train is not used for the manufacturing of worst-case drug products selected for cleaning validation then, cleaning validation of three batches for the worst product which is coming into contact with the particular equipment shall be performed. In such cases, the acceptance criteria of that particular train shall be referred to.

• • For the Worst case swab positions of certain typical instruments refer to swab identification points.

• • If the new equipment enters in equipment train, the impact analysis shall be carried out as per the new equipment evaluation form.

4.0      CLEANING VERIFICATION (CLEANING VALIDATION) :

• • The cleaning verification approach will be also applied while introducing/ replacing any equipment on the train, after appropriate evaluation.

• • On the basis of evaluation, verification will be performed if required for particular equipment until the cleaning procedure has been validated.

• • Cleaning verification for new equipment will be established for the removal of target product residue and approved detergent.

Click to read: SOP on Internal Audit and Self Inspection

• • Cleaning verification will establish/demonstrate the proper removal of target product residue, approved detergent by which it will not be expected to alter the safety, identity, strength, purity, and/ or quality of subsequent drug products being manufactured on the same equipment.

• • The following criteria shall be adopted :
    • Selection of swab position based on the difficult-to-clean location of equipment or history for worst-case sampling.

• • • The Analytical Method adopted shall be qualified for the sensitivity and swab recovery.

5.0     CLEANING TECHNIQUES (CLEANING VALIDATION) :

• • The equipment used in the tablet and capsule area is cleaned with common cleaning technology.

• • It consists of routine manual cleaning with potable water, followed by manual removal of adhered powder using a nylon brush and cleaning agent of 2% a self-foaming neutral cleaner, and then the surfaces are rinsed with potable water followed by purified water.

• • The surface is dried by wiping with a clean lint-free cloth or using filtered compressed air.

• • The cleaning process, when used between batches of the same product the only ‘visually clean’ criteria, should be followed in the equipment cleaning, such procedures will not be validated.

Click to read: Annual Product Review (APQR / APR / PQR)

• • WATER QUALITY– Water used for the cleaning of manufacturing equipment is Potable water and Purified water.

• • ANCILLARY EQUIPMENT – Ancillary equipment is utilized along with the main equipment illustrated in the equipment train.

• • They aid in the manufacturing process in terms of product transfer, excipient holding, and granulating solution preparation.

• • Examples of ancillary equipment are solution tanks, agitator assembly, and scoops.

• • Cleaning validation will be established for ancillary equipment.

6.0      EVALUATION OF CLEANING PROCEDURE (CLEANING VALIDATION):

• • To evaluate the cleaning procedure and to give evidence of cleaning effectiveness following methods will be used:
    • Visual inspection
    • Swab sample
    • Rinse sample ( where it is applicable e.g. Where the swab can’t reach)

• • This validation master plan shall properly validate the method used for the sample analysis.

• • The visual examination will be carried out when the cleaning procedure is finished.

• • Only after a thorough visual check has been conducted will swab sampling be done.

• • The next procedures must be followed if a visual check, swab sample, or rinse sample reveals unsatisfactory cleaning results.

• • • The failing cleaning procedure will be revised.

• • • The investigation will be performed and documented in the validation summary report. The revised cleaning procedure will be validated.

• • • Unsatisfactory visual inspection results will require re-cleaning using the existing cleaning procedure.

• • • Proper cleaning must be verified prior to the use of the equipment for manufacturing. Swab or rinse samples may be used to verify the re-cleaning.

For Cleaning Validation Protocol Click here

Note:

Fluidized bed dryer (FBD) bags are examples of equipment that is difficult to clean and hence should be dedicated so as to avoid sampling from the fluid bed bag during cleaning validation.

• • Equipment that, after the cleaning, has passed visual inspection, but has subsequently failed to meet the analytical or microbiological acceptance criteria for a swab or rinse sample will require re-cleaning using the existing cleaning procedure.

• • Data gathered in verifying the re-cleaning can not be used for the validation of the cleaning procedure.

• • If the failed equipment was used in the manufacturing of products, the effect of the unsatisfactory analytical or microbiological result must be investigated prior to the release of the affected products.

• • The production department in consultation with Quality Assurance will initiate an investigation as to the causes of the unsatisfactory results.

• • Sampling and analytical methods will depend on the nature of the residue and manufacturing equipment. The cleaning validation protocols will specify sampling techniques and locations.

Click to read: Microbial Culture Management (SOP)

• • Rinse samples can be applied to equipment that can hold solvent/water and are used between successive rinse steps to evaluate the effectiveness of the rinsing steps.

• • Swabbing is the preferred sampling technique since it is used for establishing the levels of residues of moderately or insoluble active ingredients, cleaning agents, and microbial bioburden.

• • Swabbing of the product contact surface of manufacturing equipment must include “ hard to clean” areas.

• • Most equipment will be swabbed in 3-5 locations, depending on the equipment size, accessibility, and complexity. Equipment with a small surface area will be swabbed in 1-3 locations.

  • Instructions for swabbing will be specified in each validation protocol for each piece of equipment.

  • The procedure will specify the following.

    • Type and amount of solvent used to extract the swab

• • • Swabbing technique

• • • The dimension of equipment surface area to swabbed (e.g.10 cm x 10 cm)

• • • Holding time and conditions for swab samples prior to testing.

  • Samples will be stored in appropriate containers tightly sealed and identified with the following information

    • Equipment identification / Location

• • • Product name and strength

• • • Batch number

• • • Sampled by and date of sampling.

7.0       ACCEPTANCE CRITERIA FOR CLEANING VALIDATION :

• • GENERAL

  • The cleaning procedure is considered validated when the acceptance criteria, as specified in the protocol, have been met.

• • The failure of individual sampling points will be investigated and based on the investigation, corrective actions will be taken that may require further follow-up or further validation.

• • The calculation of MACO shall be done based on the individual equipment train.

• • The results shall be compared with the individual MACO of each train as applicable.

• • The total carryover of API and cleaning agents shall be evaluated against the worst MACO out of all possible combinations of manufacturing and Packing.

• • Vitamins and minerals products shall not be considered for MACO calculation.

• • If acceptance criteria changes then cleaning validation should be re-evaluated with the new limits.

• • Introduction or replacement of any new equipment, which leads to an increase in the surface area where the cleaning procedure is similar then the cleaning validation should be re-evaluated with the new surface area.

• • Largest Daily Dosage in mg (Average Wt. x LDD in number dosages) to be considered for higher strength of the product.

“For Cleaning Validation Protocol Click here”

• • VISUAL INSPECTION FOR CLEANING VALIDATION :

  • After the cleaning of the equipment, a visual inspection will be performed prior to another sampling.

• • Therefore, a visual inspection will be part of the cleaning validation acceptance criteria for all equipment. The clean dry equipment must contain no visible residue.

  • ACTIVE RESIDUE:

  • The calculation of active residue after cleaning will be based on the product contact surface area.

• • This approach is based on the Largest daily dose. LDD is defined as the amount of the drug product (mg/day), that a person can be exposed as a contaminant in another pharmaceutical product without experiencing any adverse health or pharmacological effects.

• • The calculation for carryover is based on the assumption that only a fraction (1/1000) of the smallest daily dose of product “A” can be carried over to a maximum allowed daily dose of product “B” manufactured in the same equipment.

• • The factor of 1/1000 was obtained based on oral drug products that are pharmacologically inactive and safe at 1/1000 of their normally prescribed dosage.

                     Use the following formula for determining the residue level.

                    MACO = (STD X SBS X 1000 X 1000 X SF) / LDD

                    Where,

                   MACO= Maximum allowable carryover (in mg)

                   STD = Smallest therapeutic dose of any product manufactured in the equipment train (in mg).

                   SBS = Smallest batch size of any product manufactured in equipment train. (in kg).

                   SF = Safety factor 1/1000 for oral dosage product.

                   LDD = Largest daily dose of any product manufactured in equipment train.

                     (Avg. wt x nos. of dose, in mg )

                 Consider the Calculated MACO or 10 ppm whichever is less.

• • CLEANING AGENT FOR CLEANING VALIDATION :

  • The residue limit for product contact surface area/part for cleaning agents is calculated based on their toxicity data.

• • For the determination of the cleaning agents’ residue level, the worst-case study will be considered for each piece of equipment.

• • Use the following formula for determining the residue level. (Refer to Annexure-1 for the calculated limit for the Cleaning agent)

                    MACO = (ADI x SBS) / LDD = {( NOEL x 70 kg) x SBS X SF} / LDD

                     Where,

                    MACO= Maximum allowable carry over (in mg)

                    ADI = Acceptable daily intake (NOEL x 70 kg) x SF

                   SBS = Smallest batch size of the any product manufactured in equipment train. (Product-B) (in kg).

                   NOEL = No Observed Effect Level (LD50 x 5 x 10-4 gm/kg/day)

                   SF = Safety factor (1/1000)

                  LDD = Largest daily dose (Avg wt x no. of dose, in mg ) of any product manufactured in equipment                                             train(Product – B)

• • MICROBIAL TEST FOR CLEANING VALIDATION :

  • After cleaning procedures were finished and the designated hold time for the total aerobic microbial count had passed, swab samples were immediately taken from the area where the product came into contact with the surface.

• • Below mentioned the limits for the microbiological bio-burden criteria for the product.

Product, Equipment Contact Surface	Microbiological bioburden, cfu / 100 cm2
	Total Microbial count	Pathogens
Limit	NMT 50 cfu	Absent

• •   HOLD TIME STUDY FOR CLEANING VALIDATION:

  • Keep the equipment idle for 72 hrs. in dirty condition to establish the effectiveness of cleaning,

• • Equipment shall keep idle condition after cleaning for 72 hrs. and take the microbiological swab and analyzed it.

• • Consider as the worst case and microbial load should remain well within the limit to establish the expiry of cleaning in view of microbiology,

• • Hold time of Dirty equipment shall perform on only for one batch.

• • Hold time Clean equipment shall perform only for one batch.

For Cleaning Validation Protocol Click here or Visit the Article – Format for Cleaning Validation Protocol-CV

For the basics of Cleaning Validation. CLICK HERE