Cleaning validation ensures the implementation of an efficient cleaning procedure, which excludes “cross-contamination” between different products or different batches of the same product.
The cleaning procedure is effective in reducing, to predefined maximum allowable limits, all kinds of contamination from an item of equipment or a manufacturing area following processing. The means of evaluating the effectiveness of cleaning will involve sampling cleaned and sanitized surfaces and verifying the absence of product residues, cleaning residues, and bacterial contamination.
A master plan is the basis of the cleaning validation program, which describes the overall approach of cleaning validation. This includes the matrixing philosophy involved and the rationale associated thereto. Once the products and pieces of equipment are identified for use in the validation study, trials may start.
Some worst-case scenarios may also be considered to challenge the cleaning procedure, for example, having the product dried on the surface to make the cleaning difficult or applying the effect of weekends and holidays on the cleaning schedule, and so on.
A brief review of the activities to establish a comprehensive cleaning validation program is given below.
Cleaning Validation Program
Product grouping:
Based on formulation and dosage form, potency, toxicity, and solubility, all products are grouped. The broad groups may then be divided into subgroups according to the formulation and process types. After the grouping, the worst-case product is selected from each group. The worst-case product from each group may be the least soluble, the most toxic, or with the highest concentration of active ingredients. However, there is no hard and fast rule for the selection of worst-case products. In some situations, a combination of these parameters may also be used.
Equipment grouping:
Equipment of similar design and function is typically collected in one group for the validation study. In case of similar cleaning procedures are implemented, validation can be conducted on the largest- and smallest-scale equipment separately.
Cleaning methods grouping:
The grouping of cleaning procedures may be appropriate; however, the validation of the cleaning procedure may also be conducted independently of the equipment for which it is used.
Cleaning agents grouping:
Systems may also be subdivided on the basis of cleaning agents utilized on those systems when considering product formulation and equipment groupings. Incidentally, the use of a single cleaning agent will greatly minimize the work required to determine if residues of the agent remain after cleaning.
Residues and Residue Removal
Types of residues:
Physical and chemical properties such as solubility, hydrophobicity, and reactivity of residues affect the ease with which they are removed from surfaces. It is therefore important to first identify the substance to be cleaned.
Cleaning agents:
It is necessary to know the ingredients of a cleaning agent. This is important because when cleaning agents are used to aid cleaning, their removal must also be demonstrated to ensure the proper cleaning of surfaces. Once the ingredients are known, validation personnel must then determine the worst-case ingredient in the cleaning agent.
Cleaning Cycle Development
Cleaning agent selection:
Selection criteria for cleaning agents should be the suitability of removing product residues and low toxicity. Besides these, the ingredients of the selected cleaning agent should also be known so that the cleaning of the reagent itself can be proven.
Cleaning parameter selection:
The most important cleaning parameters are time, temperature, cleaning agent concentration, and cleaning action, for example, impingement, sheeting, rinsing, and so on. By evaluating each cleaning step, the removal of residues can be determined and thus the need to add, delete, or modify a cleaning step can be decided as well.
Standard operating procedures:
A draft-cleaning procedure should be in place prior to starting the cleaning validation. Once a successful validation is accomplished, the final standard operating procedure for cleaning must be completed with details such as time, temperature, concentration, and cleaning action.
Operator training:
Formal training of operators includes reviewing and understanding the cleaning SOPs, qualified apprenticeship, and ensuring that training is successful. Operators must also understand the process of cleaning and the equipment they are cleaning.
Sampling Techniques and Analytical Methods
Swabs and wipes:
Swabs and wipes are widely accepted sampling techniques. Their advantages are that they dissolve and physically remove samples, are economical, allow sampling of the defined area, are usable on a variety of surfaces, and are applicable to active ingredients, microbial and cleaning agents. However, there are some limitations involved with swabs and wipes: for example, they may introduce fibers and material to the sampling area; sometimes the design of the swab may also inhibit the recovery and specificity of the method; and they are difficult to use in crevices, pipes, or large vessels.
Rinse sampling:
The advantages of rinse sampling are the following: ease in sampling, coverage of large areas in samples including sampling of unique surfaces, being adaptable to on-line monitoring and fewer technicalities involved than swabs, and so on. Restrictions include a possible decrease in test sensitivity, inability to detect residue locations, inadequate homogenization of residues, and minimum information about actual surface cleanliness in some cases. Due to the criticality of rinse volume, usually, the entire piece of equipment is used for rinsing, such as a vessel.
Direct surface monitoring:
The benefits of direct surface monitoring are that it is fast, noninvasive, and economical. There are some limitations, however; for example, there are some prejudices and some techniques are not available yet. Visual examination of equipment for cleanliness immediately before use is a requirement by cGMP regulations. It is a form of direct surface analysis. Other commonly used methods of monitoring include pH, conductivity, total organic carbon (TOC), titration, high-performance liquid chromatography (HPLC), thin-layer chromatography (TLC), capillary zone electrophoresis, Fourier transform infrared (FTIR), atomic absorption, ultraviolet (UV) spectrophotometry, and so on.
Limits and Acceptance Criteria
- The most important element of a good cleaning validation program is the determination of limits and acceptance criteria. When determining the limits, care must be taken so that they are achievable by the analytical methods available for the specific product and active ingredient, are practical for the actual cleaning situation to be validated, and are scientifically rationalized and verifiable.
- The most commonly used basis for setting the acceptance limit is a mathematical calculation that allows a certain therapeutic dose to carry over into each dosage unit of the next product. The actual numerical limits are based on the pharmacological potency of the product, the toxicity of the residue, and the analytical limit of detection.
Ongoing Monitoring of Cleaning
- Besides inspection of each piece of equipment to ensure cleanliness before use, additional verification can also be done. This depends largely on the complexity of the equipment.
- Automated cleaning methods may not require ongoing verification; however, semi-automated processes and manual cleaning usually need periodic verification and determination of the reproducibility of the process over time.
Change Control
- Changes made to cleaning SOPs, analytical methods, detergents, equipment, product formulation, etc. should fall under the auspices of the change control policy of the company.
- Formal documentation will be required to make changes to these items. Changes performed under the change control policy will require reconfirmation of the original cleaning validation results. In case the change is deemed to be fundamental to the grouping philosophy or to the cleaning method, the change may require revalidation, which may differ from verification only by the amount of sampling.
GUIDELINES
U.S. FDA Guidelines
FDA has clearly expressed expectations that industries have to fulfill. The basic requirements, as per FDA, are as follows:
- A written procedure on how cleaning processes will be validated.
- Clearly outlined responsibility for performing and approving validation study, acceptance criteria, and revalidation requirements.
- Approved written protocols describing the study to be performed, system or piece of equipment, sampling procedures, testing methods, and so on.
- Execution of the protocols in accordance with the written commitment and recording of the results.
- A final validation report with all available data, duly approved by higher management, declaring whether or not the process has been successfully validated.
Health Canada Guidelines
According to Health Canada, the objectives of the cleaning validation are as follows:
- One should verify the effectiveness of the cleaning procedure for the removal of product residues, degradation products, preservatives, excipients, and/or cleaning agents so that analytical monitoring may be reduced to a minimum in the routine phase.
- Cleaning procedures must strictly follow carefully established and validated methods.
- Appropriate cleaning procedures must be developed for all product-contact equipment used in the production process. Consideration should also be given to noncontact parts into which the product may migrate (e.g., seals, flanges, mixing shaft, fans of ovens, heating elements, etc.).
- Relevant process equipment cleaning validation methods are required for biological drugs because of their inherent characteristics (proteins are sticky by nature), parenteral product purity requirements, the complexity of equipment, and the broad spectrum of materials that need to be cleaned.
- Cleaning procedures for products and processes that are very similar do not need to be individually validated. This could be dependent on what is common, equipment and surface area, or an environment involving all product-contact equipment.
EU-GMP Guidelines
The European Union guidelines also describe cleaning validation in the following way:
- Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure. The rationale for selecting limits of carryover of product residues, cleaning agents, and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable.
- Validated analytical methods with the sensitivity to detect residues or contaminants should be used.
- The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant.
- Normally only cleaning procedures for product-contact surfaces of the equipment need to be validated. Consideration should be given to no-contact parts. The intervals between use and cleaning as well as cleaning and reuse should be validated. Cleaning intervals and methods should be determined.
- For cleaning procedures for products and processes, which are similar, it is considered acceptable to select a representative range of similar products and processes. A single validation study utilizing a “worst-case” approach can be carried out, which takes account of critical issues.
- Typically, three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.
CLEANING VALIDATION PROTOCOL - (WORST CASE)
INTRODUCTION
Cleaning validation ensures the implementation of an efficient cleaning procedure, which excludes “cross-contamination” between different products or different batches of the same product. “The process of providing documented evidence that the cleaning method of the equipment and ancillary utensils employed within the facility consistently controls potential carryover of product, cleaning agents and extraneous material into a subsequent product to a level which is below predetermined levels.”
OBJECTIVE
- The objective of this protocol is to define the cleaning validation studies and acceptance criteria for the cleaning procedures used to clean process equipment used in the manufacturing facility at the Pharmasky.
- To demonstrate the effectiveness of cleaning procedures on the direct product contact surface, a worst-case challenge is applied that will evaluate the most difficult to remove residuals from the most difficult-to-clean areas of the equipment surfaces.
- This protocol will also aim to establish appropriate maximum holding times for dirty equipment prior to cleaning.
SCOPE
To evaluate the acceptability of the cleaning procedure used in the cleaning of equipment using well-established analytical and microbiological methods to determine the chemical and microbiological residue after cleaning the equipment. This document covers the protocol of cleaning procedures for production and packing equipment.
RESPONSIBILITY
Validation Officer:
Production:
Quality Control:
Quality Control (Microbiology):
Head – Quality Assurance:
Engineering:
SELECTION OF WORST CASE
- Due to the complexity of manufacturing and packing of multiple products using the same equipment a Bracketing approach was applied to prioritize the Cleaning Validation Program based on scientific rationale.
- This approach evaluates the overall cleaning requirement of the product range and concentrates the validation effort to develop Worst Case situation, where common cleaning procedures are followed for a similar type of equipment.
- The list of products manufactured should include in separate Attachment detail of names of the products, active ingredients used in manufacturing, their solubility in water, Strength, Minimum batch size, Maximum batch size, Average weight, and LD50.
- The Worst Case is considered on the basis of the following factors:
- Water Solubility
- Toxicity
- The concentration of Active Ingredient
- Batch Size in units
- The detailed list of equipment/vessels etc, their ID, and cleaning procedures should prepare in a separate Attachment.
CLEANING VALIDATION PROCEDURE
Swab Sampling Method
- Equipment are cleaned as per the respective cleaning SOPs followed during product changeover.
- Swab samples are collected from the predefined locations of all the equipment as per the sampling procedure described to estimate the residue content of the previous product.
- The quantity per swab is analyzed as per the Validated Analytical method.
- Calculate the total content of Active material for sampled area per swab.
- A correction factor based on the Spike Recovery Studies shall be applied to the swab results.
- The above procedure shall be repeated for three runs using the same cleaning procedure(s) as used during product changeover for all equipment.
- A cleaning validation program shall be performed on worst-case products in a particular equipment group.
- As and when the worst-case product is changed or the acceptance limits are changed (decreased), the same shall be validated.
- If the acceptable limit as per the Dose criterion comes out to be more than 10 ppm then to make acceptance criteria more stringent, 10ppm criterion shall be considered as acceptance criteria
Rinse Sampling Method
- Equipment are cleaned as per the respective cleaning SOPs followed during product changeover.
- Rinse samples allow the sampling of a large surface area. In addition, inaccessible areas of equipment cannot be routinely disassembled.
- The strongly preferred method for difficult-to-access equipment.
- May indicate a false result when the residue needs mechanical or physical action to remove from the surface. For example, when the contaminant is not soluble or occluded in the equipment.
- The residue can be diluted below the level of detection if large rinse volumes are used.
- Rinse volume shall be decided based on the lowest detection level as per Analytical method validation.
EQUIPMENT CLEANING PROCEDURE
Equipment shall be cleaned as per the respective cleaning SOPs followed during product changeover. The equipment and their cleaning procedures used in the manufacturing area should have separate Attachments. Swabs of the cleaned equipment shall be taken as per the sampling points (should have separate Attachment).
SAMPLING METHOD
Selection of Sampling Method
- Swab sampling shall be considered as the sampling method.
- Justification for swab sampling: Looking to the Design and Size of the equipment, swab sampling shall be considered the main method for validation; however, rinse will also be taken wherever necessary. Most difficult-to-clean locations are selected for sampling to determine the efficacy of cleaning.
- Advantages of swab sampling:
- Direct evaluation of surface contamination
- Insoluble and poorly soluble substances may be physically removed
- Hard-to-clean but accessible areas are easily incorporated in the final result.
Swab Sampling Procedure
- Swab samples shall be taken after the final cleaning of the equipment, and once the equipment qualifies the visual inspection test.
- Swab sampling shall be done in the following manner.
- Sampling area: 10 cm × 10 cm. = 100 cm2
- Sampling patterns: Wipe the defined area in both directions as shown in the figure. Apply only one time. Do not rub the surface into & fro movement. Refer the typical diagram to collect the sample-using swab.
- Required numbers of swabs shall be applied in this manner at defined locations.
- Swab the specified area and store in a stoppered test tube.
- Put the identification tag on the sampled test tube and sent it to QC for testing.
Rinse Sampling Procedure
Rinse samples shall be taken after the final cleaning of the equipment, and once the equipment qualifies the visual inspection test.
Rinse sampling shall be done in the following manner.
Sampling Procedure: Rinse the whole internal product contact surface with a measured quantity of purified water. Rinse the sample collected in a cleaned 100 ml amber glass bottle from the outlet of the equipment. After collection rinse the sample put the identification tag on the sampled bottle and send it to QC for chemical residue testing.
ESTABLISHMENT OF ACCEPTANCE CRITERIA
- The cleaning procedure shall be considered validated, when the acceptance criteria, as specified in the protocol, are met.
- Failure of individual sampling points will not necessarily mean that the cleaning method is inadequate. Each deviation shall be investigated and based on the investigation, corrective actions will be taken that may require further follow-up or further validation.
Visual Inspection
- After cleaning of equipment visual inspection shall be verified and reported in the report. Equipment should be visually clean and dry and must contain no visible residues.
- The visible internal equipment surfaces and all critical and difficult-to-clean parts are optically free from residue and the color of the final rinse water is comparable to purified water.
Maximum Allowable Carryover (MACO)
Based on Therapeutic Daily Dose:
To make acceptance criteria more stringent, the longest chain of equipment used in manufacturing is considered for calculation Maximum Allowable Carry Over (MACO) is calculated for the products using the following formula:
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Based on Toxicological Data:
In cases in which a therapeutic dose is not known (e.g. for intermediates and detergents), toxicity data may be used for calculating MACO. Calculate the NOEL number (No Observable Effect Level) according to the following equation and use the result for the establishment of MACO.
The safety factor (SF) varies depending on the route of administration. Generally, a factor of 200 is employed when manufacturing APIs to be administered in oral dosage forms.
General Limit: (NMT 10 ppm)
- If the calculation methods based on therapeutic doses or toxicological data result in unacceptably high or irrelevant carryover figures, or toxicological data for intermediates are not known, the approach of a general limit may be suitable. The general limit is often set as an upper limit for the maximum concentration (MAXCONC) of a contaminating substance in a subsequent batch.
- The concentration (CONC) of the investigated substance which can be accepted in the next batch, according to dose-related calculations, is:
MACO
CONC = -----------
MBS
MACO: Maximum Allowable Carryover: acceptable transferred amount from the investigated product ("previous"). Calculated from therapeutic doses and/or toxicity data.
MACOppm: Maximum Allowable Carryover: acceptable transferred amount from the investigated product ("previous"). Calculated from general ppm limit.
CONC: Concentration (kg/kg or ppm) of "previous" substance in the next batch. Based on MACO calculated from therapeutic doses and/or toxicity data.
MAXCONC: General limit for maximum allowed concentration (kg/kg or ppm) of "previous" substance in the next batch.
MBS: Minimum batch size for the next product(s) (where MACO can end up)
- A general upper limit for the maximum concentration of a contaminating substance in a subsequent batch (MAXCONC) is often set to 10 ppm. If the calculated concentration (CONC) of the previous product (based on MACO calculated from therapeutic doses/toxicity data) exceeds the general upper limit (MAXCONC), then the MAXCONC level will be the limit.
- Establish MACOppm, based on a general limit, using the following equations.
MACOppm = MAXCONC × MBS
Estimation of Acceptance Limit for Each Rinse:
- The Acceptance limit for each rinse is calculated according to the respective equipment surface area using the following formula:
MACO (mg) × Total contact surface area of equipment (c㎡)
mg / Rinse volume = -------------------------------------------------------- Total contact surface area in c㎡
The microbial counts per swab sample should not be more than 50 CFU/Swab and the fungal count should be absent per swab.
CLEAN EQUIPMENT HOLD TIME STUDY
Objective
- The objective for establishing a time limit between equipment cleaning and reuse is to ensure that the equipment remains clean till the next use. This needs demonstrate that there is no microbial proliferation in cleaned equipment during storage.
- This time limit depends on
- Level of protection provided to the equipment after cleaning.
- Environmental control and work practices.
- Nature of product to be manufactured by using the subjected equipment.
Procedure
- Clean the equipment as per respective cleaning SOP and shall be kept at a designated place and with the required class of cleanly ness.
- Zero-hour swab samples shall be taken as per the surface swab sampling procedure given below.
- The equipment shall be closed and kept in prescribed environmental conditions at a designated place.
- Swab samples shall be collected at 24hrs, 48hrs, 72 hrs and 96 hrs intervals for microbial limit test
- Swab Sampling Procedure: Area shall be swabbed with a 55 mm diameter Teflon template with straight (vertical & horizontal) strokes with sterile swab residue rinsed in saline solution. The swab shall be kept in 10ml saline solution and the test tube is identified with location and equipment name and sent to the micro department for microbial testing.
- The acceptable microbial contamination limit is based on the environmental monitoring Limits.
- Cleaned equipment surface sample (product contact surface only) test results should demonstrate an absence of pathogenic organisms.
- Recommended limits for surface microbial contamination of the equipment installed/stored in different cleanliness class areas should comply. Cleaning SOP Based on the data generated, the limit for maximum storage time after cleaning before reuse shall be established.
RE-VALIDATION
Re-validation shall be carried out if:
- Addition of new equipment
- Addition of new product (Solubility of new product is less, and Potency is lower than a worst-case product.)
- Change of cleaning method
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