INTRODUCTION:

Validation is a term that first appeared in the United States in 1978.The concept of validation has expanded through the years to embrace a wide range of activities from analytical methods used for the quality control of drug substances and drug products to computerized systems for clinical trials, labelling or process control. Validation is founded on, but not prescribed by regulatory requirements and is best viewed as an important and integral part of cGMP.¹

Cleaning validation is documented evidence with a high degree of assurance that one can consistently clean a system or a piece of equipment to predetermined and acceptable limits.

The objectives of good manufacturing practices (GMP) include the prevention of possible contamination and cross contamination of pharmaceutical starting materials and products.² Cleaning validation in a Manufacturing process have to be designed and carried out in a way that it prevent cross-contamination as much as possible. Since most pieces of equipment are being used to manufacture different products, cleaning procedure must be able to remove residues from equipment to an acceptable level.³

In pharmaceutical industry there is a great need of cleaning of equipment apparatus and processing area. Cleaning validation helps in analytical investigation of a cleaning procedure. The basic reason behind the process of good, effective, consistent cleanliness is to avoid contaminated substance of product made in the same equipment. The purpose is to provide high quality pharmaceutical products to our patients.⁴

Types Of Validation:

Pharmaceutical validation has four major types.

· Process validation

· Equipment validation

· Analytical method validation

· Cleaning validation

Process Validation:

Process Validation is defined as the collection and establishing the data evidence from the design stage from the beginning to the end of production. USFDA exaggerated process validation as “Establishing documented evidence which provides the high degree of evidence that a specific process will consistently produce a product, meeting its predetermined specifications and quality characteristics. Process validation may also be defined as the collection and evaluation of evidence, that is being followed by the process design stage throughout production, and establishes scientific evidence that a process is capable of consistently delivering standard quality products.⁵

Equipment Validation:

Validation of equipment’s is known as qualification. Equipment validation is divided into installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ). An IQ documents specific static attributes of a facility or item to prove that the installation of the unit has been correctly performed and that the installation specifications of the manufacturer have been met. After installation it must be ensured that the equipment can deliver operating ranges as specified in the purchase order. This is called OQ. The PQ’s are concerned with proving that the process being investigated works as it is supposed to do.⁶

Analytical Method Validation:

The purpose of analytical validation is to verify that the selected analytical procedure will give reliable results that are adequate for the intended purpose. Analytic method validation encompasses a variety of parameters. These are as follows:⁷

• Accuracy

• Precision

• Repeatability

• Reproducibility

• Specification

• Linearity

• Range

• Detection limit

• Quantitation limit

Cleaning Validation:

It is documented evidence with a high degree of assurance that one can consistently clean a system or a piece of equipment to predetermined and acceptable limits. Cleaning validation is most commonly used in the pharmaceutical industry for the cleaning of process manufacturing equipment. The focus of cleaning validation is those cleaned surfaces that, if inadequately cleaned, could potentially contaminate the product subsequently manufactured in that same equipment. This primarily covers product contact surfaces in the cleaned equipment. Cleaning validation is not performed only to satisfy regulatory authorities. The safety of patients is the primary objective, and product contamination presents serious liability issues for any pharmaceutical manufacturer or contract organization.⁸

OBJECTIVES:

The objective of the cleaning validation is to verify the effectiveness of the cleaning procedure for removal of product residues, degradation products, preservatives, excipients, or cleaning agents as well as the control of potential microbial contaminants.⁹

The cleaning procedure must be validated for the following reasons:

· It is a requirement of the customer. - it ensures the purity and safety of the product.

· It is a regulatory requirement in Active Pharmaceutical Ingredient (API) product.

· It also assures from an internal control and compliance point of view the quality of the process.^10,11

Regulatory Requirements for Cleaning Validation:

The FDA (Food and Drug Administration) establishes the regulations and policies relating to pharmaceutical grade products distributed commercially in United States. These regulations are called current Good Manufacturing Practices (cGMP) and are classified in Title 21, part 211 of the Code of Federal Regulation (CFR). The applicable laws at this time are general and somewhat vague, and are centered around 21 CFR 211.67 that states: “Equipment and utensils be cleaned, maintained and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality or purity of the drug product”. According to this law, every pharmaceutical and food industry should follow the cleaning validation programme to avoid finished product malfunctioning, contamination, and cross contamination.¹²

Why Cleaning Validation?

To ensure that there are no risks associated with cross contamination of active ingredients or detergents/sanitizers, cleaning procedures must be validated.¹³

Cleaning effectively is a critical component of quality assurance and GMP patient safety. Ineffective cleaning can lead to adulterated product, which can be contaminated by the previous product, by cleaning agents and by other extraneous materials introduced into, or generated by the process.¹⁴

Mechanism of Contamination:

Cross contamination with active ingredient:

One of the actual dangers in cross contamination of active ingredients is that, after contamination the outcome is a multiple active ingredient product instead of single active ingredient product. Depending on medical effects, the contamination may enhance the action or negate the action or contaminant may have an entirely different medical and health effects.

Microbiological contamination:

This form of contamination is particularly disingenuous because the contamination may develop at any time, even after cleaning. A large contributing factor is the storage of equipment in a wet or damp condition. This creates a natural environment in which bacteria can thrive.

Contamination by miscellaneous other materials:

Regardless of the usual or anticipated list of potential contaminants in a pharmaceutical operation, a number of less likely materials can also contaminate products. A partial list contains equipment parts for eg. filling equipment, bristles from brushes used in packaging, excipients, paper filters, micron filters, fibers and rubber particles from gloves, cleaning aids such as brush bristles, cloth, and cotton fibers from rags and wiping materials, lubricants etc.

Contamination by cleaning or sanitizing agents:

Some pharmaceutical operations may find it unavoidable to use fairly toxic and hazardous materials for cleaning purpose for stubborn residues. This is especially true when it comes to the manufacture of active pharmaceutical ingredients (APIs). These materials represent a potential threat as contaminant of product. It seems obvious that one effective and best way of dealing with this potential problem is to use cleaning agents with the lowest possible toxicity that will still be efficient in removing the residue in the given cleaning situation. The same factors also apply to sanitizing agents used to wipe down cleaned equipment’s.^15,16

Cleaning Mechanisms:

Cleaning is the process of removing an unwanted substance or contaminant from a manufacturing surface. There are a number of mechanisms that remove or assist in the removal of contaminants from equipment surfaces.¹⁷

The various cleaning mechanisms include:

Dispersion:

Dispersion involves the wetting followed by desegregation and then the formation of suspension of solid particles in water. This mechanism is like emulsification, difference is dispersion being used for cleaning of solid residues.¹⁸

Solubilization:

Solubilization is basically same as solubility the difference is it involves the addition of some substance to pure solvent to make the residue soluble, such as addition of surfactant to the purified water or pH modifier to make residue in the ionized or unionized hence soluble.¹⁹

Solubility:

Solubility here is the dissolution of the contaminant in a liquid medium or solvent. For instance some component (salt) might be soluble in water while other in hexane. However the rate of solubility, insoluble form left and solvent used for cleaning is considered in solubility.²⁰

Emulsification:

This process basically involves the breaking an insoluble liquid residue into tiny droplets and then making those droplets suspended throughout the water or any other specific solvent.²¹

Hydrolysis:

This involves the cleavage of different bonds in an organic molecule. Hydrolysis is a very effective cleaning procedure because it converts the large water insoluble molecule into smaller water soluble molecule because the smaller molecule formed is slightly more polar but the resultant hydrolyzed residues might be either water soluble or solubilize at the pH of the cleaning solution. Thus after the hydrolysis cleaning with water or any other solvent with specific pH may be used.²²

Oxidation:

Oxidation involves the cleavage of various organic bonds by the strong oxidizing agent such as sodium hypochlorite. The oxidants cleaves organic molecule at various linkages in the larger molecule which leads to small molecules that are more polar and increase the water solubility of the degraded components. The effect is similar to that of hydrolysis, except that the phenomenon of oxidation is more universal (and less specific) than hydrolysis.²³

Cleaning Agent Selection:

Water:

It is the all-purpose solvent. If water alone will effectively clean the product without undue time or physical effort to remove the residues, by all means employ water alone. For many, however the water alone requires an unacceptable increase in time to get the cleaning accomplished. For these individuals, one of the other approaches must be for these people, one of the other approaches must be pursued.

Solvent:

These are typically applied in processes where solvent usage is already called for by the manufacturing process. For example, mother liquors are typically used as the solvents for cleaning of APIs. As the mother liquors is already known to dissolve the primary residue, there is little risk in employing if for cleaning.

Commodity chemicals:

In this, chemicals such as NaOH can be used for cleaning as well. Like their solvent counterparts, there may be hazard issues, effluent issues associated with these materials. Their typically high alkalinity or low acidity, however, often makes them helpful in inactivation processes. However, these chemicals lack the detergency of a formulated cleaning agent and they may be difficult to rinse, taking larger volumes of water to rinse free from systems than would a formulated cleaning agent.

Formulated cleaning agent:

Formulated cleaning agent it is the largest class of cleaners. This category includes solvent-based formulations and aqueous formulations. Typically formulated cleaning agents can include one or more alkalinity or acidity sources, surfactants builders, sequestrants, chelants and either a solvent or water. For industrial applications, unlike consumer-use products, these materials are formulated to be low foaming and therefore are more readily rinsable and are appropriate for high impingement or high turbulence cleaning.^13,24

Cleaning Procedure:

Cleaning procedures should be sufficiently detailed to eliminate the possibility of any inconsistencies during the cleaning process. It is vital that the equipment design is evaluated in detail in conjunction with the product residues to be removed, the available cleaning agents and cleaning techniques when determining the optimum cleaning procedure for the equipment.

Equipment parameters to be evaluated:

· Identification of the equipment to be cleaned

· Difficult to clean areas

· Property of materials

· Ease of disassembly

· Fixed or not

Residues to be cleaned:

· Cleaning limits

· Solubilities of the residues

· Length of campaign

Cleaning agent parameters to be evaluated:

· Preferably materials that are normally used in the process

· Detergents available (as a general guide, minimize use of detergents unless absolutely required)

· Solubility properties

· Environmental considerations.

· Health and safety considerations

Cleaning techniques to be evaluated:

· Manual cleaning

· CIP (Clean-in place)

· COP (clean-out-of-place)

· Semi-automatic

· Automatic

· Time considerations

· Number of cleaning cycles^25,26

SAMPLING TECHNIQUES:

The selection of either of these techniques must be consistent with sound scientific judgment and must support the objective of the study, which is to demonstrate that the amount of residual material in the equipment has been reduced to acceptable levels.

There are three known sampling methods

· Direct surface sampling

· Swab sampling

· Rinse sampling

Direct Surface Sampling:

It involves the determination of the type of sampling methods used and its impact on the test data to check the interference of the sampling material with the test. Therefore, early in the validation program, it is crucial to assure the sampling medium and solvent if they are satisfactory and be readily used. The advantages of direct sampling are that areas hardest to clean and which are reasonable, acceptable, can be evaluated, leading to establishing a level of contamination or residue per given surface area.

Swab Sampling:

Swabbing (or direct surface sampling) method or swab sampling does not cover the entire equipment surface area, therefore, sites must be chosen with care. It is important that, as a minimum, the swab sites represent worst-case locations on the equipment and that the result is then extrapolated to account for the total product contact surface area. The solvent used for swabbing should provide good solubility for the compound and should not encourage degradation.

Rinse Sampling:

Sampling and testing of rinse samples for the residual active ingredient is a commonly adopted method to evaluated cleanliness. This is a fairly convenient method in many cases and requires control over the solvent used for rinsing, the contact time, and the mixing involved. The solvent should be selected based on the solubility of the active ingredient and should either simulate a subsequent batch of product or at least provide adequate solubility.²⁷

REVALIDATION:

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

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

· Changes in the formulation and/or process of products

· Changes in the cleaning procedure

· New products

· Changes in the formulation of detergents

· New detergents

· Changes in the raw material sources

· Modifications of equipment.

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.^8,28,29

Advantages of Cleaning Validation:

· Reduction in utility cost.

· Market recall is avoided.

· Easier maintenance of equipment.

· Avoidance of capital expenditures.

· Reduction in rejections and reworks.

· Reduce accident and results in safety.

Disadvantages of Cleaning Validation:

· This is a time consuming process.

· The process for manufacture is often complex and costly.

Applications of Cleaning Validation:

· Depletion of quality cost:

· Preventive expenses are costs brought about to avoid failures

· External failure costs associated with non-compliant conditions

· Estimated costs of inspection, testing and quality assessment.

· Internal failure costs

· Better consumer quality:

Through proper cleaning validation, market recall is evaded which results in better consumer care and quality of the product. Quality costs are divided in to four categories. They are:

· Preventive costs.

· Appraisal costs.

· Internal failure costs.

· External failure costs

· Assuring quality:

Cleaning validation and optimized process are key for affirming product's grades. Also, they are vital tools in GMP's without them acquiring quality is not possible.

· Safety

Calibrating working instruments and conditions by means of validation promote operation's safety. Since validation is elegantly standardized, they favour safety.^30,31

CONCLUSIONS:

This review gives an idea about the cleaning validation in pharmaceutical industry. Clean environment and clean operations is the heart of pharmaceutical activities. Cleaning validation is an essential component of GMP. Four basic requirements of GMP are safety, identity, strength and purity which can be achieved by cleaning process and its proper validation. and this article primarily covers all aspects related to cleaning validation like regulatory requirements for cleaning validation, mechanism of contamination, cleaning mechanisms, cleaning procedure, sampling procedure, cleaning agent selection.

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Received on 03.05.2022 Modified on 19.05.2022

Asian J. Pharm. Ana. 2022; 12(3):197-202.

DOI: 10.52711/2231-5675.2022.00033

Department of Quality Assurance, Kisan Vidya Prasarak Sanstha's,

Institute of Pharmaceutical Education, Boradi 425405.