badoo

Badoo is best app to meet the new peoples in world wide platform and make friend, online dating, chatting. It is free app for android windows and black berry mobile.  

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

HPLC Column

How to regenerate the HPLC Column and improve the efficiencies? Or Regeneration of HPLC column

 

Regeneration Procedure:

Following steps shall be performed
First, open all the HPLC column frits from the both ends and wash frequently with mixture of water and diluted nitric acid. If required the sonicate the frits for 20-30 minutes in sonicator. Then tighten the frits as usual and perform the HPLC column washing in below mentioned sequences

Name of Solvent                                      Time required for flushing
Methanol                                                 20 minutes
Water                                                      30 minutes
Methanol                                                 60 minutes
Acetonitrile                                               25 minutes
Chloroform                                              30 minutes
Acetonitrile                                               25 minutes
Methanol                                                 30 minutes
Water                                                      30 minutes
Methanol                                                 20 minutes

How to check the column efficiencies of regenerated HPLC column?
HPLC equipped with pump and UV detector along with suitable integrator system

Chromatographic condition

Mobile Phase                           :               Acetonitrile: Water (40:60)
Flow rate                                 :               1.0 mL/min.
Column Temperature              :               At ambient
Injection volume                       :               5 µl
Wavelength                             :               254 nm
Run time                                  :               25 min.

Test solution for column performance check:

Take 1.0 mL of Benzene and Toluene in 100 mL volumetric flask and make up the volume up to the mark with mobile phase. Further pipette out 10 mL solution and transferred in 100 mL volumetric flask and make up to the mark with mobile phase.

Inject three replicate injection of above test solution and check the system suitability parameters of all three replicate such as %RSD, RT of solvents peak (Benzene and Toluene), tailing factor and theoretical plates.

column chromatography HPLC

How to regenerate the HPLC Column and improve the efficiencies? Or Regeneration of HPLC column

Regeneration Procedure:
Following steps shall be performed
First, open all the HPLC column frits from the both ends and wash frequently with mixture of water and diluted nitric acid. If required the sonicate the frits for 20-30 minutes in sonicate. Then tighten the frits as usual and perform the HPLC column washing in below mentioned sequences

Name of Solvent                                      Time required for flushing

Methanol                                                 20 minutes
Water                                                      30 minutes
Methanol                                                 60 minutes
Acetonitrile                                               25 minutes
Chloroform                                              30 minutes
Acetonitrile                                               25 minutes
Methanol                                                 30 minutes
Water                                                      30 minutes
Methanol                                                 20 minutes

How to check the column efficiencies of regenerated HPLC column?

HPLC equipped with pump and UV detector along with suitable integrator system

Chromatographic condition
Mobile Phase                           :               Acetonitrile: Water (40:60)
Flow rate                                 :               1.0 mL/min.
Column Temperature              :               At ambient
Injection volume                       :               5 µl
Wavelength                             :               254 nm
Run time                                  :               25 min.

Test solution for column performance check:

Take 1.0 mL of Benzene and Toluene in 100 mL volumetric flask and make up the volume up to the mark with mobile phase. Further pipette out 10 mL solution and transferred in 100 mL volumetric flask and make up to the mark with mobile phase.

Inject three replicate injection of above test solution and check the system suitability parameters of all three replicate such as %RSD, RT of solvents peak (Benzene and Toluene), tailing factor and theoretical plates.

Process Validation in Pharma

Process Validation in Pharma
The purpose of this SOP is to define the approach to be followed to establish documented evidence that a specific process will consistently produce a result meeting its predetermined specification and quality attributes.

Approaches to Process Validation: Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.

There are three approaches to process validation.
Prospective Validation
Concurrent validation
Retrospective validation

Prospective Validation (PV): Prospective validation shall be performed on processes of API for new drug substance, new manufacturing process, new route of synthesis, change in manufacturing location, change of equipments (unlike equipments with respect to existing equipments), change in utilities, change in critical process parameters and change in final specification. Prospective validation should extend to those operations determined to be critical to the quality of the drug substance. 

For prospective process validation, following criterion shall be considered:
Three consecutive successful production batches shall be considered.
Minimum three consecutive batches shall be kept for stability study at
- Long Term Stability (25°C ± 2°C / 60% ± 5% RH) and
- Accelerated  condition (40°C ± 2°C / 75% ± 5% RH). 
Batches can be released, after the completion of prospective validation with consecutive three batches and the satisfactory compliance of minimum three months Accelerated stability data.

Concurrent Validation (CV): Concurrent validation shall be performed on processes of API for:
When data from replicate production runs are unavailable because only limited number of API batches have been produced, API batches are produced infrequently, API batches are produced by a validated process that has been modified for following changes e.g.
Vendor change for key starting material, Process changes that shall have no impact on the API quality, Change in in-put qty. of intermediates or raw materials proportionally with respect to validated process of API, Solvent qty. to be increased or decreased for purification of API, Modification in existing equipments.

For concurrent process validation, following criterion shall be considered

Three consecutive successful production batches shall be selected.
Minimum one batch among of the selected batches for concurrent validation, shall be kept for stability study at  Long Term Stability (25°C ± 2°C / 60% ± 5% RH).
Prior to completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches.

Retrospective Validation (RV): Retrospective validation can be conducted based on the historical data of batches, for well established processes that have been used without significant changes to API quality due to:
Equipment changes
Changes in raw materials,
Systems changes
Facilities changes
For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches should be taken if the number of process run are less than the ten and it should be justified and documented.
Selected batches for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient number to demonstrate process consistency.

For retrospective process validation, following criterion shall be considered for the existing process:

Critical quality attributes and critical process parameters have been identified.
Appropriate in-process acceptance criteria and controls have been established.
There have not been significant process / product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability.
Impurity profiles have been established for the existing API.
Retain samples can be tested to obtain data to retrospectively validate the process.

Validation Documentation: A written validation protocol should be established that specifies how validation of a particular process will be conducted. The protocol should be reviewed and approved by the quality unit (s) and other designated units. The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted (e.g. prospective, retrospective, concurrent) and the number of process runs. A validation report that cross-references the validation protocol should be prepared, summarising the results obtained, commenting on any deviations observed and appropriate conclusion. Any variations from the validation protocol should be documented with appropriate justification.

Process Validation Protocol: Process Validation Protocol shall consist of the following points:

1. Protocol Approval
2. Overview

1.        Objective

2.        Purpose and Scope

3.        Role and Responsibility

4.        Validation Team

3. Process details of API.

1.        Process  flow diagram of  API and Intermediates stages

2.        Batch Production and Control Records (BPCR) of API and Intermediates.

3.        Sampling Plan for process validation.

4.        Critical in-process  parameters and specification of API and Intermediates. 

5.        Critical process parameters in-process of  API and Intermediates stages.

6.        Solvent usage details in process of API and Intermediates stages.

7.        Water quality used in process of API and Intermediates stages.

8.        Specification of API and Intermediates.

9.        Packing and Storage details of API.

4. Equipment Details.
5. Validation Procedure
6. Acceptance Criteria
7. Stability plan for selected validation batches
8. Revalidation Criteria
9. Documentation

1.        Compilation (Format designs for the In-process, Intermediate and the API for  exhibit batches)

2.        Summary Report (Summarising  validation data)

3.        Conclusion and Approval (for observations, justification, action and  approval / rejection of the Validation.)

Validation report shall be generated based on the activities performed according to the protocol, Recorded observations
Summary ( summarising the stability samples details, validation activity etc., Justification / Recommendation (for any deviation and / or for process improvement), Conclusion (for comment on approval or rejection of the process validation)

Periodic Review of Validation Systems: Process and system shall be periodically evaluated to verify that they are still operating in a valid manner and where no significant changes have been made to the system or process. The quality shall be evaluated based on the PQR (Product Quality Review) for API. The quality review should confirm that the process or system is consistently producing material, meeting its specifications. The quality review can conclude and recommend the need for revalidation.

full name of ANZTPA

Australia New Zealand Therapeutic Products Agency

ANZTPA

Full Name of ANZTPA is Australia New Zealand Therapeutic Products Agency presently proposed for joint regulatory agency of Australia and New Zealand.

Linearity equation excel

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.

Precision in validation

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%.

LOD

Limit of Detection (LOD):

The lowest concentration of an analyze 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.

Cleaning Validation guidelines concept

Approach for selection of cleaning media or solvent for cleaning validation

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

Change control management Process

Identifying type of change

Concerned person shall, identify type of change based on need for change i.e. Temporary change or Permanent change. 

Temporary change

A temporary change shall be initiated  either  for a particular identified batch, on need basis or in accordance with the  permanent change Control procedure  for the study  of impacts  on batches. Before implementation of the proposed changes and to collect the data for the evaluation of proposed change . The recommendation of  Possible Impacts shall be complied  before the closing of  temporary change  procedure or to proceed further to Permanent change procedure.

Permanent change

A permanent change shall be initiated  with a vision of change in procedure  either with a backup of minimum three batches data with satisfactory results or  for the direct change (e.g. batch size increase for selected batch or batches) or with a recommendation of  competent authority. 

The permanent change shall be  followed by the recommendation of impacts, which shall be  complied  before the closing of change control procedure.     

Procedure for Change Control
Concerned person shall collect the change control form from the Quality Unit and fill the following necessary details of format such as
1 Existing Process for change will be done
2 Proposed Process for Change
3 Rational or Justification, why the change control to be initiate (e.g. to improve the quality of product, better control on product quality with proposed changes, recommended by regulatory bodies etc)

Filled change control & supporting proposed documents shall hand over to concerned department head for initial review, comment and acceptance of change. Then hand over to QA for Impact evaluation and approval.

After QA approval, impacted documents need to revised and change shall be implemented. QA shall review the implementation status in post review of change control for accuracy, correctness and impact of change with summarized results of batches or documents.
 

Change control types in Quality Assurance system

Change control procedure: A formal controlled documented process by which qualified representatives from appropriate discipline, review, propose and make changes to an approved system.

Temporary change: A change  initiated  for the evaluation of proposed system / procedure which has been taken with prior approval to achieve the desired goal  and allowed for one time change &  limited to a particular batch. For example, the  change in batch size, Equipment ,  part dispatch of batch etc.

Permanent change: A change initiated based upon scientific rational or historical GMP data or data generated through temporary changes.

Change Control Pharmaceuticals

Change control procedure: A formal controlled documented process by which qualified representatives from appropriate discipline, review, propose and make changes to an approved system.
 

Vendor Rating or Quality Index QIS API KSM

Vendor Rating / Quality Index Score (QIS) :

Trend analysis data shall be compiled on annual basis for all the Key starting material and critical raw material. Assessment of trend analysis shall determine the performance of the supplier to remain in the ‘Approved”.

The performance rating (trending) of the supplier in the “Approved ” shall be done by assigning scores as follows:

 Assign a score of “100” for every approved supply in year.

Assign a score of “0” for every rejected supply in year.
Assign a score of “50” for every approved supply but an adverse remark such as damage in packing, improper labels etc.

The vendor shall remain “Approved” for next year if the QI Score achieved More than 70.

The vendor rating is calculated based on following formula and example:

 Example: 

A vendor supplied total 15 batches through out the year, among of them 10 batches are approved, 2 batches are approved with adverse remark and remaining 3 batches are rejected. The QI Score is calculating as follow:

QI Score / Vendor Rating: [(n x 100) + (n1 x 50) + (n2 x 0)] / total nos. of batches supplied in year

Where,

n = Nos. of approved batches supplied in year

n1 = Nos. of approved batches supplied in year with adverse remark
n2 = Nos. of batches rejected in year

                        (10 x 100) + (2 x 50) + (3 x 0)

QI Score: -------------------------------------------------   = 73.33

                                              15
 

QI Score is more then 70, hence vendor shall remain as approved for next year.

Vendor Qualification KSM - QI Score

Vendor Rating / Quality Index Score (QIS) :

Trend analysis data shall be compiled on annual basis for all the Key starting material and critical raw material. Assessment of trend analysis shall determine the performance of the supplier to remain in the ‘Approved”.

The performance rating (trending) of the supplier in the “Approved ” shall be done by assigning scores as follows:

Assign a score of “100” for every approved supply in year.

Assign a score of “0” for every rejected supply in year.
Assign a score of “50” for every approved supply but an adverse remark such as damage in packing, improper labels etc.

The vendor shall remain “Approved” for next year if the QI Score achieved More than 70.

The vendor rating is calculated based on following formula and example:

Example: 

A vendor supplied total 15 batches through out the year, among of them 10 batches are approved, 2 batches are approved with adverse remark and remaining 3 batches are rejected. The QI Score is calculating as follow:

QI Score / Vendor Rating: [(n x 100) + (n1 x 50) + (n2 x 0)] / total nos. of batches supplied in year

Where,

n = Nos. of approved batches supplied in year
n1 = Nos. of approved batches supplied in year with adverse remark
n2 = Nos. of batches rejected in year
 

                        (10 x 100) + (2 x 50) + (3 x 0)

QI Score: -------------------------------------------------   = 73.33

                                              15

QI Score is more then 70, hence vendor shall remain as approved for next year.

Vendor Qualification KSM - API

Vendor qualification shall be done in following manner:

-          Based on vendor samples evaluation

-          Based on vendor samples performance or process simulation trial

-          Based on vendor audit

-          Based on provided filled questionnaire

-          Periodic vendor evaluation shall be done as based on vendor rating.

 

Vendor samples evaluation and performance trial: in general three vendor samples from the consecutive batches to be procured for desire material and analysis against the firm specification and method of analysis to confirm the quality.

 

After satisfactory comply of samples, performance trial will be taken for key starting material and produced API as per firm manufacturing process. This API shall be analysis against the firm API specification and it shall be kept in Accelerated stability as per ICH, to confirm the impurity profile and degradation at accelerated condition. If the stability comply satisfactory, then process package or vendor development report to be prepared for vendor.

 

Vendor audit: after satisfactory evaluation procured the filled vendor questionnaire and required documents from the vendor to evaluate the system to evaluate and study and documentation process are such as:

-          Certificate of vendor samples

-          Route of synthesis of material

-          Impurity profile

-          Solvent profile and declaration

-          GMO certificates

-          TSE / BSE Declaration

-          Process flow chart of manufacturing process

-          Specification and method of analysis of material

-          Organization chart

Based on satisfactory evaluation, vendor audit perform for assurance of quality system and process and vendor shall be approved. If the identified vendor holds a Drug Master File (DMF), ECOS or is having the product specific TGA, USFDA, MCA or any other international Regulatory approval, then based on the Vendor Questionnaire such vendors are approved directly.