Cleaning Validation of Manufacturing Vessel

Cleaning Validation Validation
  1. Scope :

This document on Cleaning Validation is intended to address special considerations and issues pertaining to the validation of cleaning procedures for equipment used in the manufacture of pharmaceutical products,

The document is intended to cover validation of equipment cleaning for the removal of contaminants associated with previous products, residues of cleaning agents as well as the control of potential microbial contaminants.

  1. Principles:

2.1 The objective of the cleaning validation is to verify the effectiveness of the cleaning procedure for removal of product residues, degradation products, preservatives, excipients, and/or cleaning agents as well as the control of potential microbial contaminants. In addition one needs to ensure there is no risk associated with cross-contamination of active ingredients.

2.2 Cleaning procedures must strictly follow carefully established and validated methods.

2.3 Appropriate cleaning procedures must be developed for all product-contact equipment used in the production process. Consideration should also be given to non-contact parts into which product may migrate

(e.g., seals, flanges, mixing shaft, fans of ovens, heating elements, etc.).

3.Validation of cleaning processes:

3.1 As a general concept, until the validation of the cleaning procedure has been completed, the product contact equipment should be dedicated.

3.2 In a multi-product facility, the effort of validating the cleaning of a specific piece of equipment which has been exposed to a product and the cost of permanently dedicating the equipment to a single product should be considered.

3.3 Equipment cleaning validation may be performed concurrently with actual production steps during process development and clinical manufacturing. Validation programs should be continued through full scale commercial production.

3.4 It is usually not considered acceptable to test-until-clean. This concept involves cleaning, sampling, and testing with repetition of this sequence until an acceptable residue limit is attained.

3.5 Products which simulate the physicochemical properties of the substance to be removed may be considered for use instead of the substances themselves when such substances are either toxic or hazardous.

3.6 Raw materials sourced from different suppliers may have different physical properties and impurity profiles. When applicable such differences should be considered when designing cleaning procedures, as the materials may behave differently.

3.7 All pertinent parameters should be checked to ensure the process as it will ultimately be run is validated. Therefore, if critical temperatures are needed to effect cleaning, then these should be verified. Any chemical agents added should be verified for type as well as quantity. Volumes of wash and rinse fluids, and velocity measurements for cleaning fluids should be measured as appropriate.

3.8 If automated procedures are utilized (Clean-In-Place: CIP), consideration should be given to monitoring the critical control points and the parameters with appropriate sensors and alarm points to ensure the process is highly controlled.

3.9 During a campaign (production of several batches of the same product), cleaning between batches may be reduced. The number of lots of the same product which could be manufactured before a complete/ full cleaning is done should be determined.

3.10 Validation of cleaning processes should be based on a worst-case scenario including:

(i) the challenge of the cleaning process to show that the challenging soil can be recovered in sufficient quantity or demonstrate log removal to ensure that the cleaning process is indeed removing the soil to the required level, and

(ii) the use of reduced cleaning parameters such as overloading of contaminants, over-drying of equipment surfaces, minimal concentration of cleaning agents, and/or minimum contact time of detergents.

4.11 At least three (3) consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. Equipment which is similar in design and function may be grouped and a worst-case established for validation.

4.Equipment & personal :

Equipment:

4.1 All processing equipment should be specifically designed to facilitate cleanability and permit visual inspection and whenever possible, the equipment should be made of smooth surfaces of non-reactive materials.

4.2 Critical areas (i.e., those hardest to clean) should be identified, particularly in large systems that employ semi-automatic or fully automatic CIP systems.

4.3 Dedicated product-contact equipment should be used for products which are difficult to remove (e.g., tarry or gummy residues in the bulk manufacturing), for equipment which is difficult to clean (e.g., bags for fluid bed dryers), or for products with a high safety risk (e.g., biologicals or products of high potency which may be difficult to detect below an acceptable limit).

4.4 In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products needs to be considered if the equipment is not dedicated.

  1. Personnel:

5.1Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures. Training records should be available for all training carried out.

5.2 It is difficult to validate a manual cleaning procedure (i.e. an inherently variable/cleaning procedure).

Therefore, operators carrying out manual cleaning procedures should be adequately trained, monitored, and periodically assessed.

6.0 Microbiological Considerations

1.0  The existence of conditions favorable to the reproduction of micro-organisms (e.g. moisture, temperature, crevices, and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive microbial contamination.

2.0 The period and when appropriate, conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.

3.0 In general, equipment should be stored dry, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.

7.0 Documentation

7.1 Detailed cleaning procedure(s) are to be documented in SOPs

7.2 A Cleaning Validation Protocol is required to define how the cleaning process will be validated. It Should include the following:

– The objective of the validation process;

– Responsibilities for performing and approving the validation study;

– Description of the equipment to be used;

– 7.3 A Final Validation Report should be prepared. The conclusions of this report should state if the cleaning process has been validated successfully. Limitations that apply to the use of the validated method should be defined (for example, the analytical limit at which cleanliness can be determined). The report should be approved by management.

8.0 Analytical Methods

8.1 The analytical methods used to detect residuals or contaminants should be specific for the substance or the class of substances to be assayed (e.g., product residue, detergent residue, and/or endotoxin) and be validated before the cleaning validation study is carried out.

9.0 Sampling, Rinsing, Rinse Samples and Detergents

Sampling:

There are two general types of sampling that are considered to be acceptable,

Direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against

direct surface sampling.

9.1 Direct Surface Sampling

(I) Areas hardest to clean and which are reasonably accessible can be evaluated by direct sampling method, leading to establishing a level of contamination or residue per given surface area.

Additionally, residues that are “dried out” or are insoluble can be sampled by physical removal.

(ii) The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover a sample accurately may be affected by the choice of sampling material. It is important to assure that the sampling medium and solvent (used for extraction from the medium) are satisfactory and can be readily used.

9.2 Rinse Samples

(I) Rinse samples allow sampling of a large surface area and of inaccessible systems or ones that cannot be routinely disassembled. However, consideration should be given to the fact that the residue or contaminant may be insoluble or may be physically occluded in the equipment.

(ii) Direct measurement of the residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.

(iii) Indirect testing such as conductivity testing may be of some value for routine monitoring once a cleaning process has been validated. This could be applicable to reactors or centrifuge and piping between such large equipment can be sampled only using rinse solution samples.

  1. Detergents:

10.1  When detergents are used in the cleaning process, their composition should be known to the user and their removal should be demonstrated. The manufacturer should ensure that they are notified by the detergent supplier of any changes in the formulation of the detergent.

10.2  Detergents should be easily removable, being used to facilitate the cleaning during the cleaning process.

Acceptable limits should be defined for detergent residues after cleaning. The possibility of detergent breakdown should also be considered when validating cleaning procedures.

  1. Last Rinse:

11.1  Water for injection should be used as the last rinse for product-contact equipment to be utilized in the fabrication of sterile products.

11.2  Purified water is considered acceptable as the last rinse for product-contact equipment used in the fabrication of non-sterile products or sterile products for ophthalmic use.

13.0 Establishment of Limits

13.1 The pharmaceutical company’s for selecting limits for product residues should be logical and based on the materials involved and their therapeutic dose. The limits should be practical, achievable, and verifiable.

13.2 The approach for setting limits can be:

following criteria (I, ii, iii):

(I) NMT 0.1% of the normal therapeutic dose of any product to appear in the maximum daily dose of the following product;

(ii) NMT 10 ppm of any product to appear in another product;

(iii) No quantity of residue to be visible on the equipment after cleaning procedures are performed.

  1. CLEANING PROCEDURE:

Cleaning Materials
0.5% SLS, 0.1% Dettol, Potable Water, Purified Water, Hot Water,
cleaning equipment: Nylon brush, dry cloth.
For Product to Product Change Over and  Batch to Batch Change Over
4.1 Remove the product label from double jacketed  manufacturing vessel
4.2 Wash the vessel with potable water scrub the vessel (Inside & outside) with the help of a nylon brush using 0.5% SLS in water.
4.3 Wash the vessel with a sufficient quantity of potable water so that all adhering material is completely removed and finally with purified water.
4.4 Clean inside surface with warm water 40°C to 50°C followed by 0.1% Dettol solution. Then wash with plenty of water to remove the Dettol completely, and then rinse with purified water.
4.6 Wipe the stand and transfer pipe thoroughly using a wet cloth.
Rinse the vessel outer surface with purified water.
 Cleaning Schedule
The equipment should be cleaned before and after every product to product and batch to batch change over. As per the above-given method.

Status label
Display the “Cleaned and Ready for Use” status label after cleaning the machine.

Table No: 

CLEANING VALIDATION RESULTS OF RINSE /SWAB SAMPLE:

  1. First Cleaning Application

 

                      1
Previous

Product

B# Next product B# Date
 

 

     
Sr # Parameters Specifications Observations/results  Remarks Sign
  Description

 

It should be clear colorless liquid, odorless and tasteless.      
1  

Ph

5.0-7.0    
2 Conductivity

 

NMT  4.7 µs      
3 Chlorides

 

Nil      
4 Odour

 

Nil      
5 Contamination of active ingredients (s) absorbance Show no absorbance      
6  

Contamination of low soluble materials (s)

Nil      
7 Contamination of cleaning agents  (s) Nil      
9  

Microbial contamination

Bio burden

≤ 100 colony forming unit (cfu)/ml, pathogen free      

 

 

PHYSICAL DETERMINATION OF VESSEL AFTER CLEANING

TEST ACCEPTANCE CRITERIA RESULT CONFORM/ NON CONFORM
Check visually the effective cleaning of the following component of mfg vessel  The mfg vessel must be visually clean  

 

Inner surface of lid Must be cleaned

 

 Inner wall of vessel Must be cleaned
Base of the vessel Must be cleaned
Blade of vessel Must be cleaned
Outlet of the vessel Must be cleaned

 

Table No: 

CLEANING VALIDATION RESULTS OF RINSE /SWAB SAMPLE:

 

  1. Second Cleaning Application
                      2
Previous

Product

B# Next product B# Date
 

 

       
Sr # Parameters Specifications Observations/results  Remarks Sign
  Description

 

It should be clear colorless liquid, odorless and tasteless.      
1  

Ph

5.0-7.0    
2 Conductivity

 

NMT  4.7 µs      
3 Chlorides

 

Nil      
4 Odor

 

Nil      
5 Contamination of active ingredients (s) absorbance Show no absorbance      
6  

Contamination of low soluble materials (s)

Nil      
7 Contamination of cleaning agents  (s) Nil      
9  

Microbial contamination

Bio burden

≤ 100 colony forming unit (cfu)/ml, pathogen free      

 

PHYSICAL DETERMINATION OF VESSEL AFTER CLEANING

TEST ACCEPTANCE CRITERIA RESULT CONFORM/ NON CONFORM
Check visually the effective cleaning of the following component of mfg vessel  The mfg vessel must be visually clean  

 

Inner surface of lid Must be cleaned
 Inner wall of vessel Must be cleaned
Base of the vessel Must be cleaned
Blade of vessel Must be cleaned
Outlet of the vessel Must be cleaned

 

Table No: 

CLEANING VALIDATION RESULTS OF RINSE /SWAB SAMPLE:

  1. Third Cleaning Application
                      3
Previous

Product

B# Next product B# Date
 

 

       
Sr # Parameters Specifications Observations/results  Remarks Sign
  Description

 

It should be clear colorless liquid, odorless and tasteless.

 

     
1  

Ph

5.0-7.0    
2 Conductivity

 

NMT  4.7 µs      
5 Chlorides

 

Nil      
6 Odor

 

Nil      
7 Contamination of active ingredients (s) absorbance Show no absorbance      
8  

Contamination of low soluble materials (s)

Nil      
9 Contamination of cleaning agents  (s) Nil      
10  

Microbial contamination

Bio burden

≤ 100 colony forming unit (cfu)/ml, pathogen free      

 

PHYSICAL DETERMINATION OF VESSEL AFTER CLEANING

TEST ACCEPTANCE CRITERIA RESULT CONFORM/ NON CONFORM

 

 

Check visually the effective cleaning of the following component of mfg vessel

 The mfg vessel must be visually clean

 

 

 

 

 

 

The inner surface of lid Must be cleaned

 

 The inner wall of vessel Must be cleaned
The base of the vessel Must be cleaned
Blade of vessel Must be cleaned
The outlet of the vessel Must be cleaned

 

15.0 Change Control/Revalidation

15.1 A change control system is in place to ensure that all changes that might impact the cleaning process are assessed and documented. Significant changes should follow satisfactory review and authorization of the documented change proposal through the change control procedure. Minor changes or changes having no direct impact on final or in-process product quality should be handled through the documentation system.

15.2 Changes which should require an evaluation and likely re-validation include but not limited to:

– Changes in the cleaning procedure;

– Changes in the raw material sources;

– Changes in the formulation and/or process of products;

– New products;

– Changes in the formulation of detergents;

– New detergents;

– Modifications of equipment.

15.3 The cleaning process should be reassessed at defined intervals, and re-validated as necessary. Manual methods should be reassessed at more frequent intervals than clean-in-place (CIP) systems.

  1. RESULTS AND DISCUSSION

Samples from three consecutive cleaning applications were tested for critical parameters. Table No.—— describes the results obtained from three individual samples. The conclusions of this report should state that the cleaning process has been validated successfully.

17.CONCLUSION

The cleaning process has been validated successfully. Three (3) consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.

 

 

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