CLEANING VALIDATION IN PHARMACEUTICAL INDUSTRY: A COMPREHENSIVE APPROACH

ABOUT AUTHORS:
Sharma A*, Vaghela J.S, Sharma P, Sharma B, Agrawal M, Jagiwala S
Department of Quality Assurance, Bhupal Nobles’ College of Pharmacy,
Udaipur- 313002, Rajasthan, India
*life4abhishek@gmail.com

ABSTRACT
Pharmaceutical manufacturers must validate their cleaning process to ensure compliance with standard regulatory authorities. Manufacturing and cleaning equipment must be designed for effective and consistent cleaning to avoid cross-contamination and the cleaning processes must be verified as effective. An effective cleaning shall be in place to provide 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. This article provide introduction on cleaning validation and the associated regulations, level/degree of cleaning, approaches to cleaning validation, elements of cleaning validation, acceptance criteria, validation protocols, validation reports.

REFERENCE ID: PHARMATUTOR-ART-1755

1. INTRODUCTION
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. The validation of procedures used to clean the equipment employed during the various steps of a manufacturing process is a clear requirement of current Good Manufacturing Practice (cGMP). Cleaning validation is primarily applicable to the cleaning of process manufacturing equipment in the pharmaceutical industry. Cleaning validation is the process of assuring that cleaning procedure effectively removes the residue from manufacturing equipment/facilities below a predetermined level.Cleaning validation is primarily used for the cleaning of process manufacturing equipment in the pharmaceutical industries. The main purpose of validating a cleaning process is to ensure compliance with standard regulatory authorities and the identification and correction of potential problems previously unsuspected, which could compromise the safety, efficacy or quality of subsequent batches of drug product produced within the equipment.

The term cleaning validation is to be used to describe the analytical investigation of a cleaning procedure or cycle. The validation protocols should reference background documentation relating to the rationale for worst case testing, where this is proposed. It should also explain the development of the acceptance criteria, including chemical and microbial specifications, limits of detection and the selection of sampling methods.

The basic reason for having good, effective, consistent cleaning procedures is to prevent the contamination of products made subsequently in the same equipment. The goal is to provide pharmaceutical products of the highest quality to our patients. This is the basic regulatory requirement as well as the goal of all of those suppliers of products and services.

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. The basic mechanisms involved in removing the residues and contaminants from the equipment are mechanical action, dissolution, detergency and chemical reaction.

• Mechanical action – It refers to the removal of residues and contaminants through physical actions such as brushing, scrubbing and using pressurized water.
• Dissolution – It involves dissolving the residues with a suitable solvent. The most common and practical solvent is water being non-toxic, economical, environment friendly and does not leave any residues. Alkaline and acidic solvents are sometimes preferred as it enhances the dissolution of the material, which are difficult to remove.
• Detergency-Detergent acts in four ways as wetting agent, solubilizer, emulsifier and dispersant in removing the residues and contaminants from the equipment.
• Chemical reaction- Oxidation and hydrolysis reaction chemically breaks the organic residues.

2. OBJECTIVE OF CLEANING VALIDATION
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 need to ensure there is no risk associated with crosscontamination of active ingredients. Cleaning procedures must strictly follow carefully established and validated methods.

It is necessary to Validate Cleaning procedures for the following reasons:

• Pharmaceutical products and API can be contaminated by other pharmaceutical products, cleaning agent & microbial contamination.
• It is regulatory requirement in pharmaceutical product manufacture the concern is the same-assurance that equipment is clean and that product quality and safety are maintained.
• It is also assure from an internal control and compliance point of view the quality of manufacture.
• To protect product integrity
• To reuse the equipment

Other Objectives
- Solvent reduction,
- Shorter cleaning times, increased equipment
- Utilization, extension of equipment life, multiproduct
- Facilities, worker safety, and cost-effectiveness.

“Equipment and utensils shall 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 beyond the official or other established requirements”.

The main objective of cleaning validation of equipment / utensils / components is to demonstrate sufficient documented evidence to ensure that the cleaning process can consistently remove residue of the subjected product below the established Acceptance Criteria.

*  Cleaning Philosophy :
Patients shall not be exposed to more than 1/1000 of the therapeutic dose of another API (as carry over residue). Usually equipment train / individual equipment / utensil and / or components are cleaned separately and are clubbed with a pre-wash and/or inspection program. Any cleaning procedure generally comprises of thorough cleaning with detergents / neutralizing agents / chelants / solvents alone / in suitable combination followed with final rinsing with Purified Water or Water for Injection. The final rinse water is then tested for the pH &/or TOC &/or conductivity in conformance with pre-defined acceptance criteria.

Fundamentally, the requirements for cleaning validation & the cleaning process are almost similar for manufacturing of drug substances and drug products. Nevertheless, the cleaning process of equipment & facility for drug substances are considered to be more complex as compared to the cleaning procedure for Drug Product. The reason behind this can be as follows:
i. Normally, the process involved in the manufacturing of drug substances & equipment used therein are more complex as compared to the manufacturing process of drug products.
ii. Generally the manufacturing process of drug substances comprises of multiple stages which involves chemical / physical transformation. This in-turn increases the probability of generation of more residues.
iii. The equipment / ancillary systems used for the manufacturing of drug substances are many a times complex, where cleaning of internal parts / surfaces / pipes may be difficult.

Considering the above mentioned differences between manufacturing of drug substances & drug product, following points shall be taken into considerations while framing a cleaning process / procedure.

a. It is very important to identification each of the potential contaminant and their clinical and toxicological effects.
b. Carryover of residue from the early steps may subsequently be removed in the latter stages (e.g. purification steps); hence in the early stages the cleaning requirement shall not be very stringent; the cleaning requirement shall become more stringent as it approaches to the final stages of manufacturing.

*  Potential Residues:
Manufacturing of drug substances involves, in general, chemical &/or physical transformation through a series of processing steps. Equipment train / equipment &/or ancillary system may be used for either multi product manufacturing or for dedicated individual products. The inadequate cleaning process/methods may lead to the fact that following residues may carry forward as contaminant in the next batch to be manufactured in the same equipment:
a. Precursors of the drug substance.
b. By-products and/or degradation products of the drug substance
c. Product from previous batch.
d. Solvents and other excipients employed during manufacturing process.
e. Microorganism
f. Cleaning agents and lubricants.

*  Cleaning Validation Policy:
It is advisable for the manufacturing facilities of drug substances to have a Cleaning Validation Policy. Responsibilities of specific department should be outlined in this and it should be approved. This policy should serve as a general guideline and direction to the company as how to deal with areas associated with Cleaning Validation.

The policy should incorporate at least, but not limited to, the following types of statements:
i. Definition &/or abbreviation of terms used during validation (i.e. rinse, flush, wash).
ii. Specifying the company policy on validation of cleaning procedures related to equipment, including ancillary.
iii. Company policy on dedication of equipment product wise (e.g. highly active / highly potent products to be manufactured on multi-product equipment).
iv. Policy for analytical validation.
v. Rationale for fix acceptance criteria.
vi. Policy on revalidation.

*   Cleaning Process Development:

Cleaning process development should be documented and should include:

• Equipment to be cleaned
• Materials required to be cleaned (in-process materials; API; raw materials; cleaning and sanitizing materials; solvents; microorganisms)
• What residues will be tested for, sampling locations, sampling methods and analytical methods
• Proposed Cleaning methodology
• Cleaning parameters and ranges; extent of equipment disassembly; extent of manual cleaning required, cleaning agents and rationale for selection.
• Determination of appropriate cleaning interval

What Residues to Test For?
1)  Actives:
- If several active ingredients are processed in a single piece of equipment, a marker active, an indicator active can be selected based on its solubility in the cleaning agent, potency, previous production experience, and R&D studies.

2)      Excipients:
- The removal of excipients can either be confirmed through analytical testing but is normally by visual inspection. The approach followed should be stated along with training requirements for individuals performing visual inspection.

3)      Cleaning Agents:
An indicator compound can be selected for analysis based on the recommendation of the cleaning agent manufacturer.

4)      Microbial Residues:
- Determined based on science and risk

*  Recovery Studies:
Recovery studies evaluate quantitative recovery of residue from both the surface to be sampled and the sampling method. The minimum recovery criteria for each surface type should be determined. Recovery values of 50% or greater are considered acceptable for rinse or swab methods of sampling.

In case of non-dedicated drug product manufacturing facility, different cleaning procedures may exist depending on the manufacturing step and nature of the next manufacturing step to be followed in the same equipment. This results in two different levels of cleaning as explained below:
*  Level 1 Cleaning
This is used between manufacturing of different batches of the same product.
Example – In a manufacturing Campaign for product A, there are 3 Batches to be manufactured as shown below.

Batch 1- Batch 2- Batch 3
For a given equipment &/or equipment train, if batch 1 in the campaign is to be followed by Batch 2 in the campaign, then a level 1 cleaning is required.

*  Level 2 Cleaning
This is used between manufacturing of different Batches of different Product and / or at the end of manufacturing campaign even if same product is planned for the next campaign.

The above two degree or level of cleaning differs from each other in terms of the degree of risk associated with it, acceptance limit, degree of cleaning & method of verifying the cleaning process, Table 1.

*  In case of Drug Substance
Different cleaning situation may arise during the manufacturing of drug products, such as;
i. Batch to batch changeover cleaning
ii. Changeover from early steps to intermediate of same product.
iii. Changeover from intermediate of one product to intermediate of another product.
iv. Changeover from intermediate of one product to final stage of another product.
v. Changeover from one final product to another final product

*  Approches to cleaning validation:
In order take lean approach to minimize validation requirements following points are taken into consideration:

• By adopting Bracketing procedure the substances are grouped.
• A worst case scenario rating is used to select the worst case in each group.
• Validation of worst case.

*  Bracketing Procedure:
The total manufacturing processes are grouped such as early step, critical step and API. Each group of processes is further grouped as per equipment usage similarities. All the processes are then divided as per the solubility and worst case scenario rating is made. If two or more equipment trains are used for a given manufacturing process, a choice of the train made for the same purpose. The combination of substance in a train can be chosen based upon one or more the following strategies, or combinations of them.

• Substances with the same cleaning procedure produce in the same train.
• Substance with low TDD/ low batch size (and the opposite), produce in the same train.
• Non toxic substance, produce in the same train.
• Substances with high solubility produce in the same train.

*  Worst case rating:

• Solubility in subjected solvent
• Maximum toxicity
• Minimum therapeutic dose
• Difficult to clean
• Lowest limit based on therapeutic dose/toxic data, batch sizes, surface areas etc.

3. ELEMENTS OF CLEANING VALIDATION
*   Establishments of acceptance criteria:
The Cleaning Validation should demonstrate that the procedure consistently removes residues of the substance previously manufactured down to levels that are acceptable and that the cleaning procedure itself does not contribute unacceptable levels of residual materials to the equipment. The limits set should be practical, achievable and justifiable. In Active Pharmaceutical Ingredient manufacture there may be partial reactants and unwanted by-products which may not have been chemically identified. Therefore, it may be necessary to focus on by-products as well as the principle reactant. Companies should decide on which residue(s) to quantify based on sound scientific rational.

*  Cleaning procedure:
Standard cleaning procedure for each piece of equipment and process should be prepared. It is vital that the equipment design is evaluated in detail in conjunction with the product residues which are to be removed, the available cleaning agents and cleaning techniques, when determining the optimum cleaning procedure for the equipment. Cleaning procedures should be sufficiently detailed to remove the possibility of any inconsistencies during the cleaning process. Following parameters are to be considered during cleaning procedures.

A.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

B.Residues to be cleaned
• Cleaning limits
• Solubility's of the residues

C.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

D.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

*  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:
A.    Swabbing (Or Direct Surface Sampling) Method
B.     Rinse Sampling Method
C.     Placebo Sampling Method

A.    Swabbing (Or Direct Surface Sampling) Method
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 represents worst case locations on the equipment and that the result is then extrapolated to account for the total product contact surface Area.

*  Advantages:

• Dissolves and physically removes sample
• Adaptable to a wide variety of surfaces
• Economical and widely available
• May allow sampling of a defined area
• Applicable to active, microbial, and cleaning agent residues

*  Limitations:

• An invasive technique that may introduce fibers
• Results may be technique dependent
• Swab material and design may inhibit recovery and specificity of the method
• Evaluation of large, complex and hard to reach areas difficult (e.g., crevices, pipes, valves, large vessels)

B. Rinse Sampling Method:
The solvent rinse occurs after cleaning has been completed. This method is not as direct as swabbing but will cover the entire surface area (and parts inaccessible to swabs). It is important to ensure chosen solvent has appropriate recovery for residues being quantified. This method allows much greater ease of sampling than swabbing. A reduced no of samples are required to generate a carryover figure.

*  Advantages:

• Adaptable to on-line monitoring
• Easy to sample
• Non-intrusive
• Less technique dependent than swabs
• Applicable for actives, cleaning agents and excipients
• Allows sampling of a large surface area

*  Limitations:

• Limited information about actual surface cleanliness in some cases
• May lower test sensitivity
• Residues may not be homogeneously distributed
• Inability to detect location of residues
• Rinse volume is critical to ensure accurate interpretation of results
• Sampling methodology must be defined since rinse sampling method and location can influence results
• May be difficult to accurately define and control the areas sampled, therefore usually used for rinsing an entire piece of equipment, such as a vessel
• Reduced physical sampling of the surface

C. Placebo Sampling Method:
Placebo sampling can be used to detect residues on equipment through the processing of a placebo batch subsequent to the cleaning process. It is appropriate for active residue, cleaning agent, particulates and microbial testing. Placebos are used primarily to demonstrate the lack of carryover to the next product. The placebo should mimic product attributes. The equipment characteristics also impact the choice of the placebo batch size.

*  Advantages:

• Placebo contacts the same surfaces as the product
• Applicable for hard-to-reach surfaces
• Requires no additional sampling steps

*  Limitations:

• Difficult to determine recovery (contaminants may not be evenly distributed in the placebo)
• Lowers analytical specificity and inhibits detect ability
• Takes longer and adds expense since equipment must be cleaned after the placebo run
• Placebos must be appropriate for each potential product
• Residues may not be homogenously distributed
• No direct measurement of residues on product contact surfaces
• The preferred sampling method and the one considered as the most acceptable be regulatory authorities is the swabbing method.

4. VALIDATION PROTOCOLS:
A Validation Protocol is necessary to define the specific items and activities that will constitute a cleaning validation study. It is advisable for companies to have drawn up a Master Validation plan indicating the overall Cleaning Validation strategy for the product range / equipment type / entire site. The protocol must be prepared prior to the initiation of the study and must either include or reference the documentation required to provide the following information:

• Background
• Purpose of the validation study
• Scope of the validation study
• Responsibilities for performing the validation study
• Sampling procedure to be used
• Testing method to be used
• Acceptance criteria
• Change control
• Approval of protocol before the study
• Deviations

5.  VALIDATION REPORTS
A validation report is necessary to present the results and conclusions and secure approval of the study. The report should include the following:

• Summary of or reference to the procedures used to clean, sample and test
• Physical and analytical test results or references for same, as well as any pertinent observations
• Conclusions regarding the acceptability of the results, and the status of the procedure(s) being validated
• Any recommendations based on the results or relevant information obtained during the study including revalidation practices if applicable.
• Approval of conclusions
• Review any deviations for the protocol that occurred.
• In cases where it is unlikely that further batches of the product will be manufactured for a period of time it is advisable to generate interim reports on a batch by batch basis until such time as the cleaning validation study has been completed.
• The report should conclude an appropriate level of verification subsequent to validation.

6. REVALIDATION
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. The review should include consideration of re-validation of the cleaning procedure. Changes which should require 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.

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.

7. CONCLUSION:
It is practically impossible to prove that production equipment is “clean” at the level of 100%. However, it is possible to prove that the traces of active product remaining spread through the equipment parts are within an acceptable limit and that we are capable of detecting and quantifying these trace levels. Cleaning validation provides a means of proving that the contamination levels have been reduced below contamination acceptance limits. It is concluded that to control the carryover of left over residue from previous batch to the next batch an effective, validated cleaning mechanism shall be in place. This shall contain a defined cleaning procedure, cleaning validation policy, a validation protocol, validated chemical and microbiological methods, different levels of cleaning depending on the criticality/ risk associated, approaches of cleaning validation and elements of cleaning validation, a change control programme, a validation report and any auditing required to ensure compliance.

- Assess each situation on its merits.

- Scientific rationale must be developed
i) Equipment Selection
ii) Contamination distribution
iii) Significance of the contaminant

- In some situation “visually clean” may be all that is required.

References:
1. Mowafak Nassani, “Cleaning Validation in the Pharmaceutical Industry”, Institute of Validation Technology, 38.
2. Sharma PP, How to practice GMPs, A Guide for CGMP Compliance along with PAT & HACCP, 2004, 5, 28-35.
3. William E. Hall, “Validation and Verification of Cleaning Processes” Hall & Pharmaceutical Associates, Inc., Kure Beach, North Carolina, U.S.A., 2003.
4. Shah DH, QA Manual, 1, 1-7.
5. Pharmaceutical Inspection Convention, “Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation and Cleaning Validation”, 2007.
6. Destin A. LeBlanc, “Validated cleaning technologies for pharmaceutical manufacturing” Interpharm / CRC, London, 1-10.
7. Alcock, P. and Motise, P .FDA statement: Human Drug cGMP Notes.
8. APIC: Cleaning Validation in Active pharmaceutical Ingredient manufacturing plants: 1999; 3-7.

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