Cleaning Validation Pharma

Cleaning Validation in Pharmaceuticals  

Cleaning Validattion In Pharma,  Purpose: To describe the procedure for carrying out cleaning validation for manufacturing equipment for the change over of the drug substance or drug intermediate

Prior to conducting a cleaning validation study on a drug substance or drug intermediate, cleaning media or solvent shall be selected for cleaning of equipments and Analytical methodology.

Approach for selection of cleaning media or solvent

The selection of the cleaning media shall be carried out based on following, and shall be documented in Analytical Method Validation Protocol and Report.

1. Solubility criteria
2. Solvent selection shall be derived from manufacturing process.
3. Based on the available literature or available information on the internet.
4. More cleaning effectiveness with optimum qty. 
5. Less hazardous
6. Cost effectiveness
7. Easy to handle and available.
8. Past experience about the process

Approach for cleaning method validation

After selection of cleaning media, Analytical Method Validation Protocol shall be executed for Cleaning Method validation and selected solvent shall be used for the same

Following parameters shall be cover in Method Validation

1. Selection of wavelength for cleaning samples on UV or HPLC
2. System precision
3. Method Precision
4. Linearity
5. Limit of Detection (LOD)
6. Limit of Quantitation (LOQ)
7. Solution stability of standard solution
8. Ruggedness
9. Swab recovery study

Procedure for to determined the cleaning method validation

Selection of wavelength:

Prepare the working standard solution of drug substance or intermediate according to its acceptance criteria.

UV: Scan the working standard solution of drug substance or intermediate in the range of 200-400 nm in UV-Visible spectrophotometer, observe the maxima absorbance at the wavelength. The wavelength shall be selected and fixed for the Analytical Method Validation for cleaning.

Note: if the absorbance of target concentration exceeds 1.00 Abs, value then UV method should not be considered for analysis. Alternative test procedure should be followed.

HPLC: Validated “Assay by HPLC” method shall be selected for the evaluation of the cleaning samples. If no validated analytical method for quantification is available then the cleaning method validation shall be performed and used.

 

System Precision:

UV/ Visible Spectrophotometer: Measure the six absorbances of working standard solution of drug substance or intermediate at fixed or established wavelength. Calculate the % RSD of the absorbance. The % RSD should not be more than 10%.

HPLC: Follow the validated “Assay by HPLC”, set the chromatographic condition on HPLC and  inject the six replicate of working standard solution of drug substance or intermediate. Measure the area response of the main peak of six replicate. Calculate the % RSD of the area response of main peak. The % RSD should not be more than 10%

Method Precision:

UV/ Visible Spectrophotometer:  Prepare the working standard solution of drug substance or intermediate according to its acceptance criteria by weighing six times separately and perform the measurements by UV. Calculate the % RSD of the absorbance. The % RSD should not be more than 10%

HPLC : Prepare separately six working standard solutions, inject individually and measure the area response of the main peak. Calculate the % RSD of the area response of main peak. The % RSD should not be more than 10%.

Linearity:

UV/ Visible Spectrophotometer: Prepare the working standard solution of drug substance or intermediate in singlet of different concentration such as 10%, 20%, 40%, 60%, 80%, 100 and 120% (minimum five different concentration shall be required) with respect to the concentration of system precision solution.  Measure the absorbance in three replicate of each concentration. calculate the linearity curve correlation coefficient (R²) between average absorbance of each working standard solution Vs Actual concentration of standard solution. The correlation coefficient (R²) should not be less than 0.99.

HPLC: Prepare the working standard solution of drug substance or intermediate in singlete of different concentration such as 10%, 20%, 40%, 60%, 80%, 100 and 120% (minimum five different concentration shall be required) with respect to the concentration of system precision solution.  Measure the area response of thr three replicate of each concentration. calculate the linearity curve correlation coefficient (R²) between mean area response of each working standard solution Vs Actual concentration of standard solution. The correlation coefficient (R²) should not be less than 0.99.

 

Limit of Detection (LOD):

The lowest concentration of an analyte in a sample that can be detected but not necessarily quantified under the stated experimental condition. The limit of detection will be evaluated based on the standard deviation of the response and slope.

The detection limit may express as:

          3.3 x δ

DL = ------------

            S

where

S = the slope of the calibration curve

δ = standard error of the linear regression

The calibration curve should be studied using samples containing an analyte in the range of DL. The standard error of the linear regression (STEYX) is used as standard deviation and it can be calculated by Microsoft Excel.

Theoretical calculate the LOD value based on the above formula and performed six replicate measurements at LOD level, calculate the %RSD. The % RSD should not be more than 10.0%.

cleaning validation.pdf

Limit of Quantitation (LOQ): The limit of quantitation is the lowest concentration of an analyte in a sample that can be quantified with acceptable precision and accuracy under the stated experimental conditions. The limit of quantitation will be evaluated based on the standard deviation of the response and slope.

The quantitation limit may expressed as:

          10 x δ

QL = ------------

             S

where

S = the slope of the calibration curve

δ = standard error of the linear regression

The calibration curve should be studies using samples containing an analyte in the range of DL. The standard error of the linear regression (STEYX) is used as standard deviation and it can be calculated by Microsoft Excel. 

Theoretically calculate the LOQ value based on the above formula and perform six replicate measurements at LOQ level, calculate the %RSD. The % RSD should not be more than 10.0%.

 

Solution stability of standard solution: Prepare the standard solution of drug substance or intermediate according to its  acceptance criteria and store at ambient temperature and perform the measurement at ambient condition for 0, 2, 4, 6, 8 and 12 hours. The percentage degradation should not be more than 10%.

 

Ruggedness: Prepare the standard solution of drug substance or intermediate according to its  acceptance criteria by two different analyst and perform the measurements in triplicate. The relative standard deviation for triplicate analysis and also overall  relative standard deviation should not be more than 10%.

 

Swab recovery study: The swab recovery shall be carried out by preparing the standard solution of known amount of analyte. It should be performed each on  Glass / SS plate of 100 cm2. The recovery from Glass / SS surface shall not be less than 80%.

Spike the solution on the glass or stainless steel plate as per following method

 

Approach for setting acceptance criteria:

The approaches for setting the acceptance criteria for cleaning are as following:
1.        No visible residue should be found on the equipment surface, after cleaning is performed.
2.        Based on the MAR calculation: MAR (Maximum Allowable Residue) of the drug substance or intermediate in any other drug substance or intermediate, which to be manufactured in the same train of equipments.

MAR of                           Min. daily dosage of A (mg) x Min. Batch output of B (kg) x 10⁶

Product A                    = -----------------------------------------------------------------------------------
in Product B (in mg)            1000 (SF)  x  Maximum daily dosage of B (mg)

            where,

1. Minimum daily dose (mg/day) of the investigated drug substance or intermediate / previous product.
2. Minimum Batch size (kg) and maximum daily dose (mg/day) for the next product (s).
3. The Safety Factor (SF) may be used for Topicals (10-100), Oral products (100-1000) and Parenterals ( 1000-10000). The MAR matrix helps in justifying the acceptance criteria for a cleaning validation.

If the MAR calculation method based on therapeutic doses, result in unacceptably high or irrelevant carryover figures, the approach of General limit: Not More Than 10 ppm may be suitable.
Total carry over (Rinse and Swab samples) of the previous product should be less than the MAR value.
The least value of the above approaches, shall be considered as a limit of cleaning. How ever the care should be taken that the selected limit should be approximately 2 times LOQ or higher, for the selected analytical method.

Identification of the sampling points for equipments:

Rational for selection of sampling points:
To choose the sampling points such that they represent worst case spots of the equipments. The worst case shall be defined based on:
Ø       Maximum product contact area of the equipments e.g  charging neck, side wall, shaft of stirrer, type of stirrer and bottom side or discharged out-let point of the equipments etc.
Ø       Design of the train of equipments

Type of cleaning samples 
Rinse Sample: Usually the API equipment shall be cleaned by several washing cycles (runs). Sometimes rinsing cycles/ runs (e.g. to rinse out the washing solvent) may follow the washing cycles. The quantitation of the amount of residue remaining in the equipment after cleaning shall be based on the last run of the routinely used cleaning procedure. 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 analysed solvent portion.

Swab Sample: During the swab sampling usually a small area (10cm2) of the cleaned equipment is swabbed with a pre-defined material and method (sampling technique and solvent). Subsequently the swab is extracted and the extract examined  by a suitable validated analytical method. The swab point shall be selected, based on hardest to clean.

Risk Assessment

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Risk Assessment

Risk Assessment

The most effective guideline to perform the risk assessment is ICH Q9., where given the appropriate methodology for risk assessment. Risk Assessment is most effective tool to identify the risk evaluation of process operation, operation procedure, analysis procedure, control parameters, production failure, equipment failure etc.

Principles of Risk Assessment:

To perform and evaluate the risk to quality shall be performed based on the scientific knowledge, practical experiences, threw the review of production process, control checks, probability of malfunction in process parameters, and affected parameters due to malfunction.

Risk Assessment Process:

Risk assessment shall be performed based on following question, but not limited to:
To identify the probability of risk
To analysis the risk, which types of risk to be occurred?
To evaluate the risk and which affected up to what extended
What and how control checks or tools to be implementing for reduction or prevent the risk?
How and up to what extended risk can be allow?
Finally to review the risk assessment report frequently or when as change to be proposed.

Responsibilities for assessment the risk

In general, Quality unites will be responsible to assessment the risk. But however it is not mandatory. Risk assessment to be performed with the help of concerned department. Who have the scientific knowledge, practical experience of system, operation, procedure etc. it can be done with the quality management system, where experts from the different areas will together to identify, evaluate and make effective system and control to reduce the probable risk.

What are the basic question to be ask for risk identification, evaluation and prevent

What might be wrong in process?
What is the probability to go wrong?
What are the possibilities of the consequences?

Risk identification:
It is a systematic use of information to find out the hazards which referring to the risk or problem. Risk identification can be done based on the historical data, theoretical analysis data, collect the information from direct concerned personnel who are perform the activity, which need to evaluate the risk.

Risk Analysis:

To make the effective qualitative or quantitative system or analysis tools, which give the help to identify the defect in process or like hood occurrence? The analysis tools must have the capability to detect, management and control on identified risk.

Risk Evaluation:

To compare the identified and analyzed risk against the risk criteria. Risk assessment to be either a quantitative estimate of risk or a qualitative description of range of risk. Risk can be determined as “Significant”, “Minor”, “Moderate”, “Major” and “Catastrophic” or “High”, “Medium” and “Low”. Risk assessment can be done based on the RPN number “Risk Probability Number”. In RPN, methodology, each risk category to be define in ascending number as 1, 2, 3, 4, 5 or 1, 2 and 3 as respective above categories.

Equation for Risk Assessment:  Risk = consequences or like hood x RPN of severity (Maximum is 5 x 5 = 25)

Identified risk or process shall be evaluate based on following statically tools  

Example for Risk Assessment
Consequences or like hood                     RPN Number (severity)
Significant                                                1
Minor                                                       2
Moderate                                                 3
Major                                                       4
Catastrophic                                            5

If the identified risk is fall significant, then risk of severity shall be as 1, which indicate the risk to be very less. If the identified risk is fall Catastrophic, then risk of severity shall be as 5, which indicate the risk to be very high, hence the preventive action to be taken to reduce the consequences of identified risk. Finally submission to be done for all identified consequences to get the cumulative RPN number. Calculated RPN number should not be more than 25. if it is, then strong corrective action to be taken to prevent or reduce the risk.

Risk Assessment in Pharmaceutical industries will be done based on following non-exhaustive tools

FEMA                                  : Failure Mode Effects Analysis
FEMECA                             : Failure Mode, Effects and Criticality Analysis
FTA                                     : Fault Tree Analysis
HACCP                               : Hazard Analysis and Critical Control Points
HAZOP                                : Hazard Operability Analysis
PHA                                     : Preliminary Hazard Analysis