Pravin N. Pandharmise*, Naiyer Shahzad, Anil Kamble and Manohar P. Bhagat
1 School of Pharmacy and Medical Sciences, Singhania University, Pacheri Bari, Rajasthan.
*Corresponding Author E-mail: firstname.lastname@example.org
Cleaning validation is very important in the pharma industry. The main objective of the cleaning validation is to avoid cross contamination of drug products by other drug products where more than one products being manufactured with different properties and adulteration of drug products with other active ingredients such as unintended compounds or microbial contamination. Also pharmaceutical manufacturers must validate their cleaning process to ensure compliance with cGMP regulations. The benefits due to cleaning validation are compliance with federal regulations, identification and correction of potential problems, previously unsuspected, which could compromise the safety and efficacy of drug products. This article provides the information about the cleaning validation for oral solid dosage form and its importance in pharma industry in brief. In many cases, the same equipment may be used for processing different products. So avoid contamination of the following pharmaceutical product, adequate cleaning procedures are essential.
Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment, which is suitable for processing of pharmaceutical products or active pharmaceutical ingredients (APIs) 1. Validations of equipment cleaning procedures are mainly used in pharmaceutical industries to prevent cross contamination and adulteration of drug products hence is critically important2. Cleaning validation is to verify the effectiveness of the cleaning procedure for removal of product residues, degradation products, preservatives, excipients and/or cleaning agents so that the analytical monitoring may be reduced to a minimum in the routine phase. In addition one needs to ensure there is no risk associated with cross contamination of active ingredients3.
Cleaning .By considering the patient is the last user of the drug products it is important to validate the cleaning process for its safety, efficacy and consistency of the drug products and equipments, which is used for the manufacturing of the oral solid dosage form.
This paper provides the review of cleaning process for oral solid dosage form and its importance in the pharma industry
The objective of the cleaning validation is to provide the assurance that to avoid the cross contamination of drug products with the other drug products and minimize the risk of contamination of drug products in future batches which is manufacturing in the same facility. For that by identifying the difficult to clean location cleaning shall be done and sampling shall be done for the same.
Cleaning validation shall be performed for the following reasons4
1. It is a prime customer requirement since it ensures the purity and safety of the product.
2. It is a regulatory requirement in Active Pharmaceutical Ingredient product manufacture.
3. It also assures the quality of the process through an internal control and compliance.
A brief outline of the various elements of a basic cleaning validation study is given below
1. Establishment of acceptance criteria
2. Cleaning procedure
· Identification of the equipment
· Characterization of the products (Previous: activity/toxicity, solubility, subsequent: dosage, lot size)
· Determination and characterization of the cleaning agents
3. Analytical method and its validation
4. Sampling Procedure and necessary validation of same
5. Validation protocol
6. Validation report
Approach for calculation of acceptance criteria for cleaning validation5
1. Based on Therapeutic Daily Dose
TDD previous x MBS
MACO = -----------------------------
SF x TDD next
MACO: - Maximum allowable carry over
TDD previous: - Standard therapeutic dose of the investigated product (in the same dosage form as TDD next)
TDD next: - Standard therapeutic dose of the daily dose for the next product
MBS: - Minimum batch size for the next product(s) (where MACO can end up)
SF: - Safety factor (normally 1000 is used in calculations based on TDD)
2. 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. Calculation so called as NOEL (No Observable Effect Level)
LD50 (g/kg) x 70 (kg a person)
NOEL = ----------------------------------------
NOEL: - No Observed Effect Level
LD50: - Lethal Dose 50 in g/kg animal. The identification of the animal (mouse, rat etc.) and the way of entry (IV, oral etc.) is important.
70 kg: - 70 kg is the weight of an average adult
2000: - 2000 is an empirical constant
From the NOEL number MACO can be calculated as follows
NOEL x MBS
MACO = ------------------------
SF x TDD next
NOEL: - No Observed Effect Level
MACO: - Maximum allowable carry over
MBS: - Minimum batch size for the next product(s) (where MACO can end up)
SF: - Safety factor
TDD next: - Largest normal daily dose for the next product
Oral products 100-1000
1. NMT 0.1% of the normal therapeutic dose of any product to appear in the maximum daily dose of the following product;
2. NMT 10 ppm of any product to appear in another product;
3. No quantity of residue to be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible.
4. For certain allergenic ingredients, penicillin’s, cephalosporins or potent steroids and cytotoxics, the limits should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.
Cleaning procedures should be sufficiently detailed to remove the possibility of
any inconsistencies during the cleaning process.
A. Equipment parameters to be evaluated
1. Identification of the equipment to be cleaned
2. Difficult to clean areas
3. Property of materials
4. Ease of disassembly
5. Fixed or not Etc.
B. Residues to be cleaned
1. Cleaning limits
2. Solubility's of the residues
3. Length of campaigns Etc.
C. Cleaning agent parameters to be evaluated
1. Preferably materials that are normally used in the process
2. Detergents available (as a general guide, minimize use of detergents unless absolutely required)
3. Solubility properties
4. Environmental considerations.
5. Health and safety considerations Etc.
D. Cleaning techniques to be evaluated
1. Manual cleaning
2. CIP (Clean-in place)
3. COP (clean-out-of-place)
4. Semi automatic
6. Time considerations
7. Number of cleaning cycles Etc.
Factors to be consider for the selection of the product for cleaning validation7
1. Toxicological / pharmacological activity of the previous product, its side products or degradants
2. Maximum daily dose of the following product
3. Microbiological growth
4. Batch size of the following product
5. Solubility, experience, difficult to remove previous product
And from the practical experience of the operator for difficult to clean of the product from the equipment surfaces.
For insoluble product selection following will be the criteria for the selection.
Table 1 Solubility8
Part of Solvents Required for 1 Part of Solute
Less than 1
From 1 to 10
From 10 to 30
From 30 to 100
From 100 to 1000
Very slightly soluble
From 1000 to 10,000
Practically insoluble, or Insoluble
10,000 and over
Following will be the criteria for the identification of the toxic products
Table 2 Toxicity9
Probable oral lethal dose for humans (mg/kg)
5 000 - 15 000
500 - 5 000
50 - 500
5 - 50
Types of contaminations
In manufacturing facility where more than one drugs manufacturing in the same area with same equipments there is the major chances of contamination of one product with other product, which will leads to synergistic action or non compatible action of the drug products. In that case cleaning of the previous product up to the acceptance level is important by considering the patient is the last user of the drug product.
Which includes machine parts, which are used, lubricants used, detergents (cleaning agents) used for the cleaning, brushes used for the cleaning etc.
Improper storage condition, moisture, temperature, crevices and rough surfaces, and maintenance work will leads to the microbial contamination.
1. FDA expects firms to have written standard operating procedures (SOP) detailing the cleaning process used for various pieces of equipment.
2. If firms have a specific cleaning process for cleaning between different batches of the same product and use a different process for cleaning between product changes, FDA expects the written procedures to address these different scenarios.
3. If firms have one process for removing water-soluble residues and another process for non-water soluble residues, the written procedure should address both scenarios and make it clear when a given procedure is followed.
4. It is required by the FDA, in the general validation procedure, that the personnel responsible for performing and approving the study should comply with the acceptance criteria and the revalidation data.
5. FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment which should address such issues as sampling procedures, and analytical methods to be used including the sensitivity of those methods.
6. It is expected that firms conduct the validation studies in accordance with the protocols and document the result of studies.
7. Final validation report is to be approved by the regulatory board which states whether or not the cleaning process is valid.
1. Rinse sampling:
It can be assumed that the active materials distributed equally in the equipments. Hence after cleaning of the equipment rinse water shall be collected. The residue amount in the equipment can be assumed to be equal to the amount of residue in the last wash or rinse solvent portion. The assumption is based on the worst-case consideration, that a further washing or rinsing run (or any reaction) would not wash more than the same amount of residue out of the equipment as the analyzed solvent portion did.
2. Swab sampling:
For swab sampling generally 25cm2 to 100 cm2 area used26. Swabbing involves using wipe or swab that is moistened with high purity water (WFI) that is typically wiped over a defined area in a systematic multi-pass way always going from clean to dirty areas to avoid recontamination - i.e. 10 side by side strokes vertically, 10 horizontally and 10 each with the flip side of the swab in each diagonal direction11. Then the quantified residue of the samples is extrapolated to the whole equipment7
Effective swabbing technique:25
In this exceptionally used sampling method,. Coin’s. (stamps) will be placed on appropriate sampling points in the equipment during the manufacturing of the previous product and during cleaning. After cleaning the contamination of the coins will be analyzed. The overall equipment contamination will be calculated by extrapolation of the coin’s contamination to the whole equipment. For quantitation the coins may be first swabbed and the samples further analyzed.
There are many analytical techniques available that can be used in cleaning validation13. But choosing the appropriate analytical tool depends on a variety of factors13, 14. The most important factor is to determine the specifications or parameters to be measured15. The limit should always be established prior to the selection of the analytical tool16-17.
There are several methods used for the analysis of the cleaning validation samples as follows
High performance liquid chromatography:
The vast majority of techniques described in the literature are for the determination of surfactants in concentrated products18,19. Analysis of anionic and cationic surfactants is done by HPLC and Capillary electrophoresis (CE), where as amphoteric surfactants are analyzed by HPLC, CD and ELSD20, 21
Presently total organic carbon is used widely in the pharmaceutical industries for various purposes22-23. TOC is determined by the oxidation of an organic compound into carbon dioxide. The oxidation can occur through a number of mechanisms depending on the instrument being used. TOC is used for the analysis of detergents, endotoxins, biological media and polyethylene glycol24.
In the case of biological drugs, the use of product-specific assay(s) such as immunoassay(s) to monitor the presence of biological carry-over may not be adequate, a negative test may be the result of denaturation of protein epitope(s). Product-specific assay(s) can be used in addition to total organic carbon (TOC) for the detection of protein residue31.
Swab accuracy determines a method’s ability to recover the compound of interest directly from the swab head.
There are various categories of accuracy/precision that need to be established as part of the method validation.
1. Solution accuracy is the measurement of the compound of interest added directly to the extraction solution. Reference standard solution is spiked directly into the diluents to prepare the three levels of concentration. Solution accuracy is performed as a control—usually in triplicate—to prove recovery of the analyte from the extraction solution. This recovery can then be compared to both swab and surface accuracy recoveries. If rinseates are being analyzed, this test is the only one needed to prove accuracy/ precision.
2. Swab accuracy determines the method’s ability to recover the compound of interest directly from the swab head. These studies are performed by directly adding standard material to the swab head and then extracting as per the analytical method. Typically, three replicate-spiked swabs are prepared at the high and low concentrations, while six replicates are prepared at the 100% level.
3. Surface accuracy determines the method’s ability to recover the compound of interest directly from a defined surface. Coupons of the defined surface material are spiked with reference standard at the three concentration levels mentioned above. The area of the coupon spiked with standard is dependent on the actual cleaning procedure and the surface area typically sampled after manufacturing.
4. Acceptance criteria should be evaluated and determined during the development of the analytical methods. Many factors influence the establishment of appropriate criteria, including the surface being swabbed, MCL, type of swab, and instrumentation. Intermediate accuracy/precision should be performed by a second analyst repeating the accuracy/ precision tests listed above. If multiple surfaces are involved in the validation, the second analyst can perform accuracy/precision on select surfaces (worst case) if appropriate.
The linearity of an analytical procedure is its ability, within a given range, to obtain test results that are directly proportional to the concentration (amount) of analyte in the sample.
A minimum of five concentration levels are typically evaluated, with duplicate injections at each level. Concentrations ranging from the limit of quantitation to 200% of the MCL are typically evaluated during validation. Acceptance criteria are generally based upon either the correlation coefficient or the coefficient of determination of the linear plot. In addition, criteria can be established around both the slope and Y-intercept of the plot.
Specificity is the ability to assess the analyte unequivocally in the presence of components that may be expected to be present.
Swab type and surface type are typically evaluated to determine if interferences are present in the method. Although each of these components is typically examined during method development, they should be included in the validation process and shown, under protocol, to have little or no interference. Swabs and surfaces are prepared as per the method without the introduction of the analyte of interest. Interference from either the swab or surface should be less than 10% of the MCL. Lower limits for specificity may be appropriate depending on the method conditions.
Limits of Detection and Quantitation:
The limit of detection (LOD) of an individual analytical procedure is the lowest amount of analyte in a sample that can be detected but not necessarily quantitated as an exact value. The limit of quantitation (LOQ) of an individual analytical procedure is the lowest amount of analyte in a sample that can be quantitatively determined with suitable precision and accuracy.
Both the LOD and LOQ should be verified by a suitable number of preparations known to be prepared near the respective limit being evaluated.4 LOD and LOQ can be estimated using a signal-to-noise approach with typical values of three-to-one for LOD and 10-to-one for LOQ.
During method validation, standard solutions are prepared at the estimated LOD and LOQ (three preparations for LOD and three preparations with duplicate analyses for LOQ). Typical acceptance criteria for LOD require that the analyte be detected in each analysis. For LOQ, the percent recovery is determined for each of the six measurements and should fall between 75% and 125% recovery. The relative standard deviation is also determined for the six measurements and should be less than 25%.
The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small but deliberate variations in method parameters and provides an indication of its reliability during normal usage.
Instrument and reagent variations, for example, may be examined as part of robustness to ensure that the method provides reliable data under varying conditions. Robustness may be determined during development of the analytical procedure, and if measurements are susceptible to variations in analytical conditions, these should be suitably controlled, or a precautionary statement should be included in the procedure.
Stability–Stock Standard, Working Standard, Working Swab:
Stability of stock standards, working standards, and working swab or rinseate samples are evaluated as part of the validation. Stability can be evaluated under various conditions such as refrigeration or protection from light, but ambient conditions are preferred. This stability period is necessary to ensure that cleaning validation samples can be collected, shipped to the testing facility, and analyzed. The length of stability is particularly important for cleaning validation sample solutions and should be at least one week old, preferably two weeks.
1. Cleaning validation procedures should be revalidated when the equipment train of the manufacturing process is changed.
2. Any changes in the synthesis of the drug substance,
3. Changes in the composition of the finished product, or changes in the analytical procedure require revalidation
Sometimes in cleaning validation studies, it is determined that not all the residue on a surface can be fully recovered, thus producing lower recoveries. In these instances, it may be necessary to apply a recovery factor. If a recovery factor is deemed appropriate, several issues must be considered before it is set:
1. Recovery factors are usually not applied if recovery results are above 70%; however, there is no standard limit.
2. Recovery factors must be set under sound scientific justification.
3. Recovery factors should not be used if recoveries are too low. (For example, if recoveries are consistently around 10%, a 10X factor would not be appropriate.)
4. Recovery factors need to be set prior to or during validation, not during routine monitoring.
5. All results used to determine the recovery factor need to be consistent and reproducible.
Effective cleaning validation maintenance program:28
Minimum three batches cleaning validation runs would be completed and after getting results with in the acceptance limit whole cleaning process would be demonstrate for sufficiently and consistently to remove the chemicals and detergents from the equipments surface during the study in order to meet the pre-established criteria. Following factors which would affect the efficiency and consistency of the cleaning program such as
1. Operator variability
2. Equipment aging and repair
3. Potential non representative results and monitoring programs
4. Changes to the product, equipment and process
1. The objective of the validation process;
2. Responsibilities for performing and approving the validation study;
3. Description of the equipment to be used;
4. The interval between the end of production and the beginning of the cleaning procedure;
5. The number of lots of the same product, which could be manufactured during a campaign before a full cleaning is done
6. Detailed cleaning procedures to be used for each product, each manufacturing system or each piece of equipment;
7. The number of cleaning cycles to be performed consecutively;
8. Any routine monitoring requirement;
9. Sampling procedures, including the rationale for why a certain sampling method is used;
10. Clearly defined sampling locations;
11. Data on recovery studies where appropriate;
12. Validated analytical methods including the limit of detection and the limit of quantitation of those methods;
13. The acceptance criteria, including the rationale for setting the specific limits;
14. Other products, processes, and equipment for which the planned validation is valid according to a "bracketing" concept;
15. Change Control/ Re-validation.
A cleaning validation program is an assessment of equipment and product and the impact of the process on process which is being used for the routine process to determination of an appropriate cleaning agent and method, determination of acceptance criteria for the residues, determination of a degree of evaluation required to validate the procedure, decisive on the residues to be tested based on solubility and toxicity, development of sampling method and analytical method development for the product for recovery and detection of residues. acceptance criteria for the validation, compilation and approval of the validation protocol, scope for the validation studies to be performed in accordance with the protocol, compilation and approvals of validation reports, documented studies, conclusions, recommendations and revalidation policy.
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Received on 23.06.2011 Modified on 30.06.2011
Accepted on 08.07.2011 © RJPT All right reserved