Cleaning Validation in Pharmaceutical

Industry
Poonam Khalate*, Bharati Chaudhari, Vivekkumar Redasani
YSPM’s Yashoda Technical Campus, Faculty of Pharmacy, Satara, 415003.
*Corresponding Author E-mail: poonamkhalate22@gmail.com
ABSTRACT:
In pharmaceutical industries there is possibilities of contamination, cross contamination, microbial contamination,
adulteration of drug with other active ingredient or contamination with other material like raw material, dust, lubricant,
intermediates and air born particle.1 Cleaning validation validate the effectiveness of cleaning procedure for removal
of excipient, product residue, degradation product and cleaning agent. Cleaning validation improves the potency and
reliability of cleaning in given pharmaceutical production and equipment. The cleaning validation is essential part of
the quality assurance. As a result, validating cleaning procedures is critical in the pharmaceutical sector to ensure the
safety, efficacy, and quality of drug batches. The purpose of this review is to provide information about cleaning
validation in pharmaceutical industry to provide better customer care and quality of product. This article will discuss
the relevance of cleaning validation in the pharmaceutical sector, and it will do so in accordance with regulatory
guidelines.2,3
KEYWORDS: Cleaning validation, Cleaning method, contamination, Sampling techniques, levels of cleaning.

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 sense7,8

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 cm 2 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:
1. Raj Pal G, Arya RKK, Joshi T, Bisht D. A review on cleaning validation in pharmaceutical industry, Journal of Drug Delivery and
Therapeutics, 2018(8); 138-146.
2. Fauziya K, Abdul Sattar K, Nutan R. A review article on cleaning validation in Pharmaceutical industries IJRPC 2020, 10(2), 205- 214.
3. Prasanna Reddy Battu, MS Reddy. RP-HPLC Method for Simultaneous Estimation of Paracetamol and Ibuprofen in Tablets. Asian J. Research
Chem. 2(1): Jan.-March, 2009;Page 70-72.
4. Murthy N and Chitra K. A review article on cleaning validation IJPSR, 2013.
5. Singh A, Sharma P. 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. doi: 10.5958/0974-4150.2019.00060.9
6. Guide to cleaning validation in API plant. Cleaning validation in Active Pharmaceutical Ingredient manufacturing plant by APIC. 1999;3.
7. Maurya S, Goyal D, Verma C; Cleaning Validation in pharmaceutical industry- An Overview PharmaTutor; 2016;4(9);14-20
8. 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.
9. Effat S, Nazanin S. R, Farhad A, Arsalan N. A, Maliheh B. T, Massoud A. Validated Stability-Indicating HPLC Method for the Determination
of Pantoprazole in the Presence of Its Degradation Products. Asian J. Research Chem. 3(4): Oct. - Dec. 2010; Page 879-884.
10. Robert A Nash and Alfred HW. A Textbook of Pharmaceutical Process Validation. 3rd edition New York: Marcel Dekker. 2003;793-820
11. Koradia SK, Shah PT, Rana RR, Vaghani SS, Pandey S, Jivani NP. Spectrophotometric Determination of Atomoxetine Hydrochloride from
Its Pharmaceutical Dosage Forms. Asian J. Research Chem. 2(3): July-Sept., 2009, page 258-259.
12. Mittal A, Parmar S, Gilani S.J, Syed S, Mohamad T. Optimization and Validation for Simultaneous Estimation of Citicoline and Piracetam in
bulk and tablet formulations using RP-HPLC method: Analytical quality by design approach. Asian J. Research Chem. 2017; 10(2):198-205.
doi: 10.5958/0974-4150.2017.00034.7
13. Agallaco J. Frederick Carelton J: A Text Book of Validation Pharmaceutical Process. Spring Publisher, third edition 2008: 525-565
14. https://www.stockmeier.com/en/products/chemicals/specialty-chemicals/home-industrial-care/non-ionic-surfactants/
15. Patel P. K, Patel NM and Patel PM. An Overview on Cleaning Validation. Int J Pharm Biol Arch. 2011;2(5):1332-36
16. Sayed Imtiaz H, Erfan Sayed A. Cleaning Validation Manual: A Comprehensive Guide for the Pharmaceutical and Biotechnology Industries.
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

Accepted on 27.08.2022 ©AJRC All right reserved
Asian J. Research Chem. 2022; 15(5):386-390.
DOI: 10.52711/0974-4150.2022.00068