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Question ans Answer on Cleaning validation in Pharmaceutical Industry

Question 1. What Is Cleaning Validation?

Answer:   To evaluate the capability of cleaning procedure  in removing the drug residue and microbiological bio burden on equipment within established acceptance criteria, through the validation of cleaning procedures.

  • To establish sufficient documented evidence to assure that, cleaning procedures can repeatedly and reproducibly remove residue of the subjected product and or cleaning agent i.e. Sodium Lauryl Sulphate (wherever applicable) – within established acceptance limit. The acceptance limit is maximum allowable quantity of product residue and or cleaning agent, which does not affect quality and safety of the subsequent product to be manufactured, by using same equipment and facility.
  • To establish acceptable time limit for storage of cleaned equipment, utensils and components after cleaning (Cleaned Equipment Hold Time Study). Equipment’s are not expected to be free from all microorganisms. The objective shall be to demonstrate that there is no microbial proliferation in equipment’s during storage.

Question 2 -What is prerequisite for cleaning Validation ?

Answer: Means  requirement  before proceeding for cleaning validation execution.

  • The cleaning shall be done by following the SOP for cleaning of equipment.
  • Three successful runs of batches or different strength of the same product shall be considered for completion of cleaning validation activity.
  • Sampling shall be done from all the pre-decided locations and as per surface area mentioned.
  • The equipment’s used for manufacturing shall be as per list of equipment’s.
  • The critical parts of equipment, which are difficult to clean, shall be considered for sampling.
  • Critical in-process control shall be evaluated with respect to the laid down specification.
  • Swab/ Rinse samples shall be analyzed as per laid down test procedures and comply with respect to the predetermined specifications.
  • Pre  Cleaning Validation requirements viz. Product details, Batch Numbers taken for validation, Equipments used for manufacturing & SOPs for cleaning and Approval status of applicable documents (STPs, GTPs, and Analytical Method Validation protocols & reports e.t.c.).
  • Analytical and sampling method shall be available.
  • Cleaning validation protocol in which outline the steps to be followed during  execution of cleaning validation studies.
  • Critical equipment parts with respect to cleaning (i.e. product contact parts) for sampling shall be identified and documented before performing the validation.
  • Cleaning procedure to be validated with three consecutive runs of recommended worst case product to check the consistency for chemical and microbiological cleanliness. (For CEHT, DHET and campaign length study, one run of worst case product shall be considered for validation).
  • During cleaning validation, swab sampling method shall be used, however, rinsing methods can also be used when swabbing is impractical and the residues are soluble. For rinse water, sample to be collected from final wash of equipment.

Question -3: What step are followed during cleaning Validation?

Answer:  Following are the steps to be followed for execution of cleaning validation programе.

  • Demonstrate that the cleaning procedure shall perform consistently according to predetermined acceptance criteria.
  • Cleaning validation shall be performed after cleaning.
  • After satisfactory visual inspection only, the equipment shall be allowed for sampling.
  • Swab samples and Rinse samples shall be collected to verify the presence of active residue content and Microbiological bio burden as per given sampling plan.
  • Samples should be taken from pre-defined locations as mentioned in this protocol.
  • All Sampling and testing reports have been made available.
  • All precautions and instructions have been followed.
  • Three runs of cleaning are required to prove that the process has been validated.
  • Worst case identification for cleaning validation -for worst case identification take  Input From BMR collect details for assessment of worst case identification.
  • Preparation and updation of equipment based matrix.
  • Preparation of ‘Worst case identification report for cleaning validation’
  • To identify the new worst case and to determine the necessity of cleaning validation, prepare the product based ‘Worst case identification report for cleaning validation’ .
  • The ‘Worst case identification report for cleaning validation’ shall evaluate the potential risk and requirement for chemical cleanliness verification (i.e. API   residues), microbial assessment, clean equipment hold time, dirty equipment hold time.

Question 4: What cleaning Validation Approach is most common in cleaning Validation nowadays?

Answer: 

Due to complexity of manufacturing and packing of multiple products using same equipment a Bracketing approach shall be applied to prioritize Cleaning Validation Program based on scientific rationale.

The approach evaluates overall cleaning requirement of the product range and concentrates the validation effort to develop Worst Case situation, where common cleaning procedures are followed for similar type (Operating Principle and Capacity) of equipment.

The Worst Case is considered on the basis of following factors:

  • Physical characteristic i.e. Solubility, Cleanability
  • Therapeutic Dose of the Product
  • Concentration of Active Ingredient
  • Equipment combination (Equipment Train)

In this bracketing approach cleaning validation of each equipment train shall be performed based upon the worst-case product selected for that equipment train.

A Matrix of products with the details of active ingredient,

  • Therapeutic category,
  • Strength,
  • Maximum daily dose (mg & No. of dosage units),
  • Batch size (kg & Lacs) and
  • Solubility

A Matrix of Equipment combination with the details of equipment name,

  • I.D. No.,
  • area,
  • capacity,
  • contact surface area,
  • equipment usage and
  • preferred rinse volume for sampling

On the basis of matrix of Products and Equipment’s, Worst Case situation (Product to Product Change Over) shall be derived. The rationale for each Worst Case shall be justified scientifically.

Rationale for the residue limit established should be scientific, logical and based upon knowledge of the material. The limits should be practical, achievable and verifiable.

Question 5:What type of  situations where cleaning procedures need to evaluated during cleaning Validation?

Answer: Cleaning shall be done in the following situations:

    • Product to Product change over
    • After every five consecutive batches of the same product
    • Production of same products in descending potency
    • After any major changes of product contact parts
    • Receiving of new equipment

 

Question 6: How to select Acceptance Criteria during Cleaning Validation?

Answer: Product Residue Contamination,Cleaning agent residue contamination and Microbial Contamination  is factor  that is used for Selection of Acceptance Criteria during cleaning validation 

1.Product Residue Contamination,

2.Cleaning agent residue contamination and 

3.Microbial Contamination

The acceptance criteria for Product Residue Contamination are as below

  • 10 ppm Criteria:

This criteria is followed to determine the maximum allowable concentration of residual API

Maximum allowable carryover in mcg/100sq.cm as per 10 PPM criteria =

      10                   B. size of next product in Kg

= ————– x————————————– x100* x 1000# x 1000# x1000#                       

    1,000,000               CSA (sq. cm)

Where

CSA – Common surface area

10/1000000- 10 ppm

100* – Factor used to convert the maximum allowable content per 100 sq.cm

1000# – Factor used to convert the maximum allowable content into ‘mcg’

  • Dose criteria:

Maximum allowable carryover (MAC) of previous product to next product is not more than 1/1000th of minimum dose of previous product in maximum daily dose of next product. Calculation of limit per swab as per this criteria is done as per the formula given below

Dose criteria=

Maximum allowable carryover in mcg/100 sq.cm as per dose criteria =

                        MEDpp (mg) X B. size of next product (units) X 100* X 1000#

= —————————————————————————————-                                  

                           1000  X MDDnp (units) X CSA (sq. cm)

Where:

MEDpp –  Minimum effective dose of previous product

MDDnp –  Maximum daily dose of next product

CSA –  Common surface area

1/1000 –  Safety factor

100*-  Factor used to convert the maximum allowable content per 100sq.cm

1000# –  Factor used to convert the maximum allowable content into ‘mcg’

  • Permitted Daily Exposure Criteria:

Maximum allowable carryover (MAC) should be based upon the Permitted Daily Exposure. The principle of MAC calculation is that you calculate acceptable carryover for your previous product based upon the PDE into your next product. Calculation of limit per swab as per this criteria is done as per the formula given below  

              PDE x mBS X 100*

MAC = ————————————           ,                              

            MDDnp (units) X CSA (sq. cm)

Where

PDE – Permitted daily exposure

mBS – minimum batch size

MDDnp – Maximum daily dose of next product

CSA – Common surface area

100*- Factor used to convert the maximum allowable content per 100sq.cm

  • Visual clean criteria: The limit as per this criteria is not more than 400 µg / 100. sq.cm
  • To arrive at the final acceptance limit using matrix approach, acceptance limit for swab shall be calculated for each permutation of product as previous & next product using above formulae. The most stringent limit out of the all the permutations shall be accepted as the limit
  • In case of active ingredient, the most stringent limit amongst 10 ppm, 1/1000th dose criteria and visual clean criteria will be used as the acceptance criteria
  • For dedicated equipment, cleaning validation shall be reduced to validate the cleaning procedure for the removal of microbiological assessment up to the predetermined acceptance criteria. The cleaning procedure must ensure that the equipment is visually clean

Note: On the basis of MAC calculation of all above mentioned criteria the minimum MAC value of the product shall be considered as a Worst Case Product.

The acceptance criteria for Cleaning agent residue contamination are as below

The rationale for selecting limits of carryover of cleaning agent (sodium lauryl sulphate) residue shall be logically based on the material involved. The limits should be practical, achievable and verifiable. On the basis of following criteria acceptance limits i.e. Maximum Allowable Carry Over (MACO) shall be established:

In case of Cleaning agent (SLS) residue, MACO shall be calculated as follows as per medical limit criteria:

                                               LD50 (g/kg) X 70(kg a person)

No Observable Effect Level =  —————————————

                                                Conversion Factor (1000)  

From the NOEL number a MACO can then be calculated according to

                                                                             NOEL X  MBS

Maximum Allowable Carry Over (mg per batch) = ————————-

                                                                               SF X MDD

Where,

LD50: LD50 value (lethal dose) of the cleaning agent i.e. Sodium lauryl sulphate

SF: Safety Factor (10000)

BS: Batch size of the next product (product B) i.e. Minimum Batch Size

MDD: Maximum Daily Dose; milligram of dosage units of the product  Btaken per day

The acceptance criteria for Microbial Contamination are as below

  • Microbial assessment

Permissible number of total microbial count and mold per 100 cm2 is 50 CFU and 10 CFU respectively

  • Clean equipment hold time (CEHT) assessment

Permissible number of total microbial count and mold per 100 cm2 is 50 CFU and 10 CFU respectively

  • Dirty equipment hold time (DEHT) assessment

Cleaned equipment: Permissible number of total microbial count and mold per 100 cm2 is 50 CFU and 10 CFU respectively

  • Campaign length

Uncleaned equipment: Permissible number of total microbial count and fungal per 100 cm2 is 100 CFU and 20 CFU respectively.

Cleaned equipment: Permissible number of total microbial count and mold per 100 cm2 is 50 CFU and 10 CFU respectively

Note:

In addition to above, shall  Also consider the following points during worst case identification

  • If the cleaning validation (Product Residue Contamination,Cleaning agent residue contamination and Microbial Contamination ) with worst case product is successfully completed on a particular equipment then for other products on the same equipment cleaning validation is not required. (The assessment and the rational shall be documented in ‘Worst case identification report for cleaning validation).
  • If the equipment identified for cleaning validation is available with various volumetric capacity and if the equipment with higher and lower capacity (With having same cleaning procedure) is already validated then no need to validate the other capacities of the same equipment (Equipment equivalency and impact assessment shall be documented).

Question 7: What is the contains of Cleaning Validation?

Answer : Contains of Cleaning Validation as follow –

1.0 Protocol Preparation and Approval Sheet 
2.0 Objective 
3.0 Scope 
4.0 Responsibility 
5.0 Validation Team 
6.0 Abbreviations and Definitions 
7.0 Cleaning Validation Approach 
7.1 Selection of Products 
7.2 Selection of Equipment’s 
7.3 Type of Cleaning after every five consecutive batches of the same product 
8.0 Pre – Cleaning Validation Requirements 
9.0 Precautions and Instructions 
10.0 Acceptance Criteria 
10.1 Product Residue Contamination 
10.2 Cleaning agent residue contamination 
10.3 Microbial Contamination 
11.0 Cleaning Validation Programme
 11.1 Selection of Cleaning Procedure 
11.2 Water Quality 
11.3 Selection of Analytical Method 
11.4 Analytical Method Validation
 11.5 Sampling Plan, Type of Sampling and Selection of Sampling method
 11.6 Evaluation of Cleaning Procedure 
11.7 Analytical Testing Procedure
 11.8 Cleaning Verification
 11.9 Ongoing Monitoring 
11.10 Ancillary Equipment 
11.11 Cleaning of Manufacturing Area
 12.0 Hold Time Studies 
12.1 Equipment Holding Studies Prior to Cleaning 
12.2 Cleaned Equipment Hold Time Studies 
13.0 Training 
14.0 Revalidation 
15.0 Deviations and Investigations 
16.0 Cleaning Validation Report  

Question 8: How to prepare  the cleaning Validation Protocol ?

Answer : The protocol shall describe about the general procedure to be followed to demonstrate the effectiveness of cleaning procedure to establish. Product Residue Contamination,Cleaning agent residue contamination (i.e. no contamination with active residues and residues of cleaning agent). The protocol shall describe about the sampling method and selection of critical equipment parts for sampling.

The protocol shall  also describe in  detailed about

  • Microbial Contamination (no contamination with bacteria and fungi)
  • Cleaning intervals and idle times on dirty Equipment hold time (DEHT), Clean equipment hold time (CEHT) studies and Campaign length study.

The protocol shall describe about the sampling method and selection of critical equipment parts for Sampling.

For  template of cleaning Validation Protocol Refer  – www.pharmaguidances.com

Question 9: How to execute Cleaning Validation Activity?

Answer:

To perform the cleaning validation in accordance with the recommendations from ‘Worst case identification report for cleaning validation’, following procedure is to be followed to execute the validation activity:

  • Check and verify the prerequisite of cleaning Validation.
  • Clean the equipment as per cleaning procedure.
  • Prior to sampling, sampler shall perform visual inspection of the cleaned equipment for the absence of particulate matter.
  • If the equipment is found visually clean then sampler shall follow the approved cleaning validation protocol for sampling method.
  • As per the recommendations from ‘Worst case identification report for cleaning validation’, sampler shall collect the samples for chemical assessment and micro assessment and submit the samples to QC for analysis.
  • QC  shall perform the analysis as per the approved analytical and microbiological method and submit the results to QA  for compilation and preparation of cleaning validation report.
  • For chemical cleanliness assessment and microbial assessment, repeat the procedure for two more consecutive runs as a part of cleaning validation program.
  • In case of result failures, QA shall initiate an investigation for root cause.

Note: In case of any change in the cleaning procedure required, a product specific cleaning procedure shall be prepared and validated.  

Question 10: What parameter is Consider during preparation of cleaning validation report?

Answer: Based on the outcome from this validation study, a report shall be prepared.Report shall contain the outcome of the validation exercise, conclusion and recommendations.

Based on the protocol of CEHT, DEHT assessment, Campaign length study and microbial assessment, shall prepare a separate study specific report.

On successful completion of cleaning validation, the respective cleaning procedure can be considered as validated for the respective equipment.

Question 11: What is the Re-validation  criteria?

Answer: The cleaning Validation shall be re-validated in one or more of following cases

  • Change of formulation procedures or quality of pharmaceutical ingredients.
  • Major changes of process parameters.
  • Change in facilities
  • Equipment changes
  • Changes in cleaning procedure
  • On appearance of new findings based on current knowledge.
  • Batch size change.
  • Implementation of these changes shall be carried out as per change control system.
  • If new product introduced in the plant which is new worst case on the equipment.
  • Change in cleaning agent.
  • Critical modifications in equipment which impacts effectiveness of existing cleaning procedure.

Question 12: What  Term that are more used in Cleaning Validation?

Answer : Some common term that is more commonly used in Cleaning Validation as follow-

Clean :The implementation of procedures to render a piece of equipment, or a system, free of adulterants and contaminants.

Cleaning Validation :The process of providing documented evidence that the cleaning methods employed within a facility consistently controls potential carryover of product (including intermediates and impurities), cleaning agents and extraneous material into subsequent product to a level, which is below predetermined levels.

Contaminant:Drug active, excipient, degradant, processing aid, cleaning agent, bio burden or foreign matter that, at a high enough level remaining after cleaning may potentially contaminate the equipment surfaces or the next product.

Dedicated Equipment/ Accessories: Equipment/Accessories only used for the manufacture of one product or one related product line.

Equipment Train:Series of individual pieces of equipment linked together for a given process which may be cleaned individually or as a process train.

Dirty Equipment Hold Time (DEHT): Elapsed time between the end of a manufacturing / packaging process аnd execution of the complete cleaning procedure.

Clean Equipment Hold Time (CEHT): Elapsed time between the end of a complete cleaning process and introduction of product for the next use.

Campaign length: Number of batches of same product and same strength processed between complete cleaning runs. During campaign manufacturing between two batches equipment and area to be cleaned as per general cleaning procedure.

Manual Cleaning :A cleaning procedure requiring operator performed critical steps (e.g., scrubbing with a brush or rinsing with a hose)

Objectionable Micro organisms :Any organisms that can cause infections, when the drug product is used as directed or any organism capable of growth in the drug product. 

Protocol:A document with agreed upon set of standards and tests.

Rinse:To clean or treat an equipment as part of a cleaning procedure.

Swab:An absorptive device used to remove a sample from a surface.

Visually Clean :Absence of visible contaminants

 Worst case:Worst case is those conditions within normal parameters most likely to give failure.

 

For More Pharma Updates Visit –https://pharmaguidances.com

About Pharmaceutical Guidanace

Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field. During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube

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