INTRODUCTION:

Validation is evidence that is backed up by documentation of a high-quality assurance of a specific pharmaceutical procedure, process, material and equipment to produce a product with its predetermined specification and quality.⁴

Cleaning validation is documented evidence which improves the effectiveness and uniformity / expectation in cleaning of equipment in pharmaceutical production. It is primarily applicable to manufacturing equipment or parts of manufacturing equipment which is difficult to clean in industry. The cleaning procedure is validated and methods are developed to determine the amount of residue present on equipment to avoid cross contamination during manufacturing.^2,5

Why Cleaning Validation is Important:

Cleaning validation's major goal is to prevent drug cross-contamination and adulteration with other APIs. So, the main purpose is the avoid contamination and manufacture a product free of any contamination with high quality assurance and patient safety concern.⁴

Objective of Cleaning Validation:

It is a prime customer requirement to ensure the purity and safety of the product to be consumed.²

It also confirms the quality of process through an internal control and compliance.⁶

Advantages of Cleaning Validation:

· Assure of quality and safety

· Product integrity

· Microbial integrity

· Cross contamination integrity

· Batch integrity

· Reduction of quality cost

· Making good business sense^7,8

Machanism of Contamination:

Cross Contamination with APIs:

When the product is manufactured they get cross contaminated with APIs of previous prepared batch of drug. The APIs, foreign chemicals and microbes are unintentionally transfer to other batch medicine with harmful effect that might affect the purity and quality of pharmaceutical.^4,9

Contamination by Cleaning Agent:

Cleaning agent with the lowest toxicity effective in cleaning the residue. Non-ionic detergent are used in cleaning of manufacturing equipment in pharmaceutical industry. There is a problem associated with cleaning agent with its composition. Many suppliers supply cleaning agent with different composition, which make difficult to evaluate the amount of residue to be cleaned. It is important to evaluate the formulation of cleaning agent to determine its efficiency of cleaning process. Contamination of cleaning agent with drug results in poor quality medicine result in patient safety related issue.^10,11

Contamination by Miscellaneous other Materials:

In pharmaceutical operation there is contamination due to various equipment parts such as micron filter, paper filter, bristle from the brushes during scrubbing, cotton thread from wiping cloth, rubbered particle from gloves and fibers from the sponge.^4,12

Cleaning Agent:

Water:

Water is a universal solvent which is used as cleaning agent in cleaning process. It is also a solvent cleanser in itself. But water alone is not used as cleaning agent as it increases the time of cleaning or more physical effort to remove the residue. So other approaches are used.¹³

Detergent:

There are various types of detergent such as cationic detergent, anionic detergent, amphoteric detergent, alkaline detergent etc. But non-ionic detergent used in cleaning of equipment to protect the product quality in pharmaceutical manufacturing. Non-ionic detergent do not ionize when dissolved in water. Due to this property, they can easily cleaned from equipment surface. They are effective against oily material. Acceptable limit should defined for detergent residues after cleaning.^14,15

Cleaning Methods:

1) Clean in Place (CIP):

The CIP entails the cleaning of a significant portion of the equipment. It is quite similar as a automated cleaning. CIP prevents the backflow and assess the recirculation of cleaning solution for its subsequent use.

There are two different types of clean in place system-

a. Single pass system-

In these new cleaning solutions is introduced in equipment to cleaned. Pre- rinse is carried out to remove soiling.

b. Recirculation system-

These systems use less water and detergent but need a larger investment, although they are problematic in particular situations owing to cross contamination.

2) Clean out of Place (COP):

Cleaning is done in these systems by disassembling parts of the equipment from their functioning areas and transporting them to a designated cleaning location. COP system consists of immersion tank and spray jets which create unsteady movement of water results in scrubbing and cleaning of parts.

3) Manual Cleaning:

The direct cleaning of equipment by trained employees by using a brushes, cloths, mops, brooms etc.

4) Semiautomated Cleaning:

Semiautomated cleaning involves the combined activity of both manual and automated. For example, before automated CIP, manually remove the gasket and fitting.

5) Automated Cleaning:

Automated cleaning is operated by automatic equipment and it consist of programmable cycle of cleaning. It does not include any personnel interferences.^16,17

Sampling Method:

Samples are collected based on their critical site which is difficult to clean. For sampling, equipment are categorized into critical site and hot spot.

1. Swab Method (Direct sampling):

In this method, fibrous material of swab is attached to the plastic stick.

Firstly, swab is pre- wetted in solvent in which residue of sampled solution is soluble. Then squeezing the swab on the side of vial to remove extra solvent from swab. Extra solvent is removed because it may leave extractable substance on the surface which leads to error in result.

Procedure:

· Choose the worst-case location of the equipment on which the sample is done in these system cleanings.

· Choose the solvent in which analyte of sample is soluble.

· Before taking the swab, it is important the surface is visually clean.

· Pre wet the swab in solvent.

· Take a swab over a surface at a fixed surface area. (i.e., 5×5 cm² or 10×10 cm²) Figure -2

· Take a swab in vertical and horizontal direction. Figure-3

· Break the swab head along with narrow swab handle with the help of side wall of vial and allow it to fall into vials. Figure-4

· Label the sample and transfer it for analysis.

Figure 1- Fibrous Material Swab

Figure 2- Template Tool for Swab Sampling

Figure 3- Swabbing Pattern

Figure-4

(A notched swab handle simplifies separating the swab head from the handle. Only the head needs to be extracted for measurement.)

Advantage of Swab sampling:

· It determine both microbial and chemical contaminants.

· It removes insoluble and poorly soluble substance from surface.

· Hard to clean but accessible areas are easily incorporated into the final evaluation.

Disadvantages of Swab sampling:

· During taking the swab, fibrous material may entre.

· Difficult to implement in large scale manufacturing equipment.

· Difficult to take swab from pipes and large complex vessels.

2. Rinse Sampling:

It is also known as indirect sampling method.

In rinse sampling, larger surface area may be sampled or inaccessible part or system that cannot be routienly disabled can be sampled and evaluated.

Procedure:

· Develop a SOP of rinse sampling by considering the design, size, shape, capacity of that equipment.

· Determine the final rinse solvent quantity.

· The most common technique is to take sample from final rinse of water during final rinse of cleaning process.

· Another method is to fill the entire part of that equipment with water and then bulk sample is taken and transfer for analysis.

Advantages of Rinse sampling:

· It gives large surface area for sampling.

· Easy to take sample.

Disadvantage:

· Residue may be insoluble.

· Inability of detect location of residue.

· Residue may not be distributed equally.

· May reduce test sensitivity.

3. Placebo Sampling:

In these cases, Placebo is acknowledged as a possible cleaning procedure as well as a possible sampling technique. The active ingredient is absent from the placebo substance, which contains all of the usual excipients. The placebo premise is that it is passed along the same conduit as the substance, therefore it has the potential to wipe off residual product along those channels.

4) Direct Sampling:

FTIR or photoelectron emission techniques are used to accomplish this. Specific spectra obtained from residue remaining on the surface will be used to directly measure the quality of the surface using the approaches. The downsides of employing these techniques include the fact that sample and analysis will be completed in one step, with no true sampling system loss.^4,7,13,18

LEVELS OR DEGREE OF CLEANING:

The level or degree of cleaning validation required depends on the undermentioned factors

· Nature of the contaminant (solubility, toxicity)

· Usage of equipment (dedicated equipment or not)

· Manufacturing stages (initial, intermediate, or final stage)

· Batch to batch change over

· Product to product change over¹¹

Level 1 Cleaning:

This is used in the manufacture of different batches of the same product. This can be illustrated by taking the example of the manufacture of 4 subsequent batches of paracetamol, say, batch 1, batch 2, batch 3, and batch 4; then, if the manufacture of batch 1 is followed by batch 2 in the same equipment level 1 cleaning is to be followed, which is not so rigorous.^19,20

Level 2 Cleaning:

This level of cleaning is used for the equipment used in the manufacture of different products of different batches or at the end of the manufacturing stage even if the same product is planned for the next batch. The above levels of cleaning, level 1 and level 2, differ from each other in terms of their risk association, acceptance limit, degree of cleaning, and even the method of verifying the effectiveness of cleaning.^20,21

Validation Protocol:

To specify the precise items and activities that will constitute a cleaning validation study, a Validation Protocol is required. It is recommended that businesses have a Master Validation Plan on hand that outlines the overall Cleaning Validation approach for the product line, equipment type, and entire site. The protocol must be prepared and approved prior to the initiation of the study and must either include or reference the documentation required to provide the following information:

· Specific Background

· Purpose of the validation study

· Scope of the validation study

· Responsibilities for performing the validation study

· Sampling procedure to be used and testing method to be used

· Acceptance criteria

· Change Control requirement

· Deviation during the study.^22,23,24

Cleaning Validation Report:

The results and conclusion of the study must be represented in a validation report in order for the study to be approved.

· A summary of or reference to the cleaning, sampling, and testing procedures;

· Physical and analytical test findings or references for the same, as well as any important observations

· Any recommendations based on the results or pertinent information gained during the study, including revalidation practises if necessary.

· Conclusions regarding the acceptability of the results and the state of the procedure(s) being validated.

· Approval of conclusions

· Review of any protocol deviations that occurred.

· If it's doubtful that more batches of the product will be created for a while, it's a good idea to generate interim reports on a batch-by-batch basis until that time comes.^24,25,26,27

Revalidation:

Revalidation of cleaning procedure to be done if,

· Substitution of existing equipment with new equipment.

· Any major modification in the equipment.

· Any change in Standard Operating Procedure of cleaning.

· Introduction of new product /manufacturing process.

· Any failure of cleanliness acceptance criteria during monitoring.^28,29,30,31

CONCLUSION:

The pharmaceutical industry is free from any contamination during manufacturing and it would be safe to consumer. With the help of cleaning validation we can achieve high level of confidence in the cleaning process. Cleaning validation minimize the cross contamination during manufacturing. Cleaning validation provide better customer care and quality of products. Cleaning validation improves effectiveness of cleaning procedure.^32,33,34

REFERENCE:

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14. https://www.stockmeier.com/en/products/chemicals/specialty-chemicals/home-industrial-care/non-ionic-surfactants/

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17. Modi P.B,.Vairale A.S, Sivaswaroop P. Development and Validation of HPLC method for determination of Ketorolac tromethamine residues on the surface of manufacturing equipment. Asian J. Research Chem. 5(2): February 2012; Page 259-264.

18. Nrusingha P. A Review on Swab sampling and Rinse sampling procedure used in Pharmaceutical industry.

19. Priyanka D.D., Chhabra G. S., Gujarathi N. n, Jadhav A. Regulatory Aspects of Cleaning and Cleaning Validation In Active Pharmaceutical Ingredients. Asian Journal of Pharmaceutical Research and Development. 2018;6(3):69-74.

20. Pharmaceutical A., Committee I., September R. Active Pharmaceutical Ingredients Committee (APIC) 2016.

21. Jadhav PA, Raut CS, Bidada JP, Buwa BB, Dhabale PN, Dhawale SC. Development and Statistical Validation of UV Spectrophotometric Method for Estimation of Griseofulvin in Tablet Dosage Form. Asian J. Research Chem. 3(2): April- June 2010; Page 404-406.

22. Kamal Hossain, Kamrun Nahar, Ehsanul Hoque Mazumder, Tony Gestier, Tanvir Ahmed Khan, Kaiser Hamid. Development of a Cleaning Validation Protocol for an Odd Case Scenario and Determination of Methoprene residues in a Pharmaceutical Manufacturing Equipment Surfaces by using a Validated UFLC Method. Research J. Pharm. and Tech 2017; 10(11): 3789-3794.

23. Chaudhari BP, Daniel K. A Validated Ultra Performance Liquid Chromatography Method for Simultaneous Estimation of Diacerein and Aceclofenac in Bulk and Pharmaceutical Formulation, Research J. Pharm and Tech 15(4): April 2022. 1467-1471

24. Ashish Singh, Pushpendra Sharma. Simultaneous Development and Validation of Analytical Methods for Cleaning Samples Analysis of Gliclazide and Meslamine in Pharmaceutical Industry. Asian J. Research Chem. 2019; 12(6):326-329.

25. Prakash B. Modi, Ajay S.Vairale, P. Sivaswaroop. Development and Validation of HPLC method for determination of Ketorolac tromethamine residues on the surface of manufacturing equipment. Asian J. Research Chem. 5(2): February 2012; Page 259-264.

26. Kishan Malviya, Monika Maheshwari, Mahendra Singh Rathore. Spectroscopic method for the quantification of residue of Tetramethylthionine chloride on swab from manufacturing equipment in support of cleaning validation. Research Journal of Pharmacy and Technology. 2022; 15(4):1499-4.

27. P.V.S. Machiraju, V.Namratha, Ch. Veerababu. Physicochemical and Biochemical Characterization of Surface Waters in Mangrove areas of Godavari Region for Assessing their Interaction with Ground waters. Asian J. Research Chem. 6(3): March 2013; Page 257-262.

28. Saish Naik, Celina Nazareth, Sanelly Pereira. A Novel HPLC cleaning Validation and Assay method for the simultaneous estimation of Perindopril and Amlodipine. Research J. Pharm. and Tech. 2020; 13(12):5919-5923.

29. Anisha Naik, Celina Nazareth, Sarvada Naik Gaonkar. Cleaning Method Development and Validation for the Simultaneous Estimation of Olmesartan and Atorvastatin by HPLC. Research J. Pharm. and Tech 2020; 13(5):2125-2128.

30. S. Janet Beula, R. Suthakaran, Y. Ramulu, M. Viswaja, G. Venkateswaralu. A Review on Cleaning Validation-Regulatory Guidelines for The Pharmaceutical Industry. Asian Journal of Pharmaceutical Research. 2022; 12(2):167-0.

31. Hapse S.A., Bhagat B.V., Wagh V.S. , Kadaskar P.T.. Cleaning Validation of Paracetamol Tablets as a Dosage Formulation. Research J. Pharma. Dosage Forms and Tech. 2011; 3(5): 215-219 .

32. Pravin N. Pandharmise, Naiyer Shahzad, Anil Kamble, Manohar P. Bhagat. Cleaning Validation for Oral Solid Dosage Form and Its Importance in Pharma Industry. Research J. Pharm. and Tech. 4(9): Sept. 2011; Page 1449-1454.

33. Narendra Chotai, Vishnu Patel, Harsha Patel, Uren Patel, Rajendra Kotadiya. Cleaning Validation Study of Amoxycillin Trihydrate. Research J. Pharm. and Tech. 2(1): Jan.-Mar. 2009; Page147-150.

34. Chaudhari B, Daniel K. A Validated RP- HPLC Method for simultaneous Estimation of Tizanidine and Nimesulide in Bulk and Pharmaceutical Formulation Research J. Pharm and Tech 2020:13(9):4207-42012

Received on 04.06.2022 Modified on 20.07.2022

Asian J. Research Chem. 2022; 15(5):386-390.

DOI: 10.52711/0974-4150.2022.00068