Get the latest updates from us for free
Mobile Apps



Apr 29, 2012

Validation of Supporting Processes in Pharmaceuticals


1.  Washing of Components

The washing of components will be validated for each load configuration in the vial washer. Cycle Development Testing and Performance Qualification testing will qualify each washing process. A separate performance qualification and cycle devel­opment testing report will be written for each load configuration. The processes will be considered validated when the acceptance criteria is met for three (3) successful consecutive runs.

Cycle Development Testing

Perform one or more cycle development test runs with vials to determine appro­priate time for each cycle (wash and rinse), temperature for each cycle, load size, WFI supply pressure, and air supply pressure.

Performance Qualification Test Functions

1.  Identify and document the quantity and placement of vials in the load configuration. Determine load configuration from Cycle Development Test studies.
2.  Prepare a full load of vials spiked with dye. Wash the vials as per the proposed operating procedure. Inspect each vial for dye residue.
3.  Spike three (3) sets of vials with NaCl solution. Allow vials to dry and then wash them per the proposed procedure. Baseline data will be established using unwashed, NaCl‑spiked vials. Test the washed vials for conductivity (NaCl) and particulate count (WFI).

Acceptance Criteria

1.  No dye residue is detected at >1 ppb in any of the washed vials.
2.  The rinse solution from each washed, NaCl‑spiked vial must have a con­ductivity <2 µmho.
3.  The rinse solution from each washed, NaCl‑spiked vial must have no precipitate when tested per USP Monograph for Sodium Chloride.
4.  Both the rinse solutions from the NaCl‑spiked and unspiked vials must have particulate counts that meet the specifications listed in USP Mono­graph for Physical Test, and Particulate Matter in Injections.
5.  The rinse solutions from the NaCl spiked and unspiked vials must meet the specifications for Water for Injection listed in USP Monograph for Water for Injection.
6.  The rinse solutions from the unspiked vials must have no more than 0.25 EU/ml.

2.  Sterilization of Components

The sterilization of components and equipment will be validated for each load configuration using the cGMP autoclave. Cycle Development Testing and Performance Qualification Testing will qualify each sterilization process. A separate Per­formance Qualification and Cycle Development Testing Report will be written for each load configuration. The process will be considered validated when the accep­tance criteria is met for three (3) successful consecutive runs.

Cycle Development Testing

Perform one or more cycle development test runs used in the load configuration to determine appropriate cycle type, temperature and dwell period, hard-to-heat items or areas, load item preparation, and minimum and maximum load configurations.

Performance Qualification Test Functions

1.  Identify and document the quantity, placement, and physical description of each component to be included in the load configuration. Determine the load configuration from Cycle Development Test studies.
2.  Perform load and chamber temperature mapping and verify that the temperature distribution in the chamber is uniform for the load configuration, and that all measured points within the load configuration receive thermal treatment sufficient for sterilization. Perform three (3) runs on the maxi­mum load and a minimum of three (3) runs on the minimum load.
3.  Perform microbiological challenge studies using the Overkill Approach Sterilization Validation. Place Bacillus stearothermophilus spores throughout the load configuration, at points where steam penetration may be incom­plete, and at hard-to-heat locations. Perform a minimum of three (3) runs on the maximum load configuration and a minimum of three (3) runs on the minimum load configuration. Perform spore quantification verification on each manufacturer’s lot of spore strips or suspensions. Perform micro­biological challenge studies simultaneously with loaded chamber heat pen­etration and distribution studies.
4.  Record the range of all process or equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during cycle Devel­opment and Performance Qualifications testing.

Acceptance Criteria

1.  During load and chamber temperature mapping, the maximum load con­figuration, the mean of the F0 values from the single slowest-to-heat point from each of the three (3) test runs minus 3 standard deviations of the these three F0 values must be greater than 20 min.
2.  During load and chamber temperature mapping, the minimum load con­figuration, the mean of the F0 values from the single slowest-to-heat point from each of the three (3) test runs minus 3 standard deviations of the these three F0 values must be greater than 20 min.
3.  During microbiological challenge studies, all Bacillus stearothermophilus spore strips/suspensions must show negative test for the growth of B. stearother­mophilus.
4.  During microbiological challenge studies, positive controls for the B. stearothermophilus spore strips/suspensions must test positive for the growth of B. stearothermophilus.
5.  During Microbiological Challenge studies, spore strips/suspension quanti­fication test must indicate that the population of each manufacturer’s lot of spore strips/suspensions is within ±50% of their labeled population.

Related: Autoclave Validation in Pharmaceuticals


3.  Depyrogenation of Components

The depyrogenation of components will be validated for each load configuration using the depyrogenation hot air sterilization tunnel. Cycle Development Testing and Performance Qualification Testing will qualify each depyrogenation process. A separate Performance Qualification and Cycle Development Testing Report will be written for each load configuration. The processes will be considered validated when the acceptance criteria is met for three (3) successful consecutive runs.

Cycle Development Testing

Perform one or more cycle development test runs with item used in the load configuration to determine appropriate cycle type, temperature and dwell period, hard-to-heat items or areas, load item preparation, and minimum and maximum load configurations.

Performance Qualification Test Functions

1.  Identify and document the quantity, placement, and physical description of each component to be included in the load configuration. Determine load configurations from Cycle Development Test studies.
2.  Perform load and chamber temperature mapping and verify that the tem­perature distribution in the chamber is uniform for the load configuration, and that all measured points within the load configuration receive thermal treatment sufficient for depyrogenation. Perform three (3) runs on the maximum load and a minimum of three (3) runs on the minimum load.
3.  Perform pyrogen challenge studies and verify through laboratory testing that the endotoxin contents of all indicators in each load are reduced by a minimum of 3 logs. Endotoxin reduction of 3 logs or greater will also ensure a greater than 12 log reduction of biological organisms.
4.  Record the range of all process or equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during Cycle Devel­opment and Performance Qualifications Testing.

Acceptance Criteria

1.  Temperature distribution thermocouples in the heat penetration and dis­tribution test studies for three (3) consecutive runs must be within ±5°C of the mean chamber temperature during the dwell period at any one print interval.
2.  During heat penetration studies, all thermocouples must receive a minimum temperature of 250°C. FH (250°C) must be calculated.
3.  The endotoxin content of all endotoxin indicators must be reduced to levels of <0.025 EU (or undetectable), or at least demonstrate a minimum of 3 log reduction for three (3) consecutive runs at half-cycle.
4.  Positive controls for endotoxin indicators must yield a minimum of 1000 EU.
5.  Negative controls for endotoxin indicators must be <0.03 EU/ml.

4.  Aseptic Filling Validation (Media Fill Studies)

Protocols will be developed to demonstrate that the product is aseptically filled into a final dosage container. These studies will consist of exposing media capable of supporting a broad spectrum of microbiological growth to all operations and procedures normally performed during the manufacturing process. Vials will be filled at the normal working volume. Each study will include filling approximately 3000 vials/ampoules. The vials/ampoules will be incubated at 20 to 25°C for 14 days.
“Worst‑case,” challenges such as personnel breaks, equipment adjustments, and additional personnel in the fill room will be incorporated into all media fill studies. Stoppers and vials or ampoules will be sterilized. The time between sterilization and the start of the first media fill will be the maximum validated storage time for sterile stoppers, vials, and ampoules, provided the media fills meet all other accep­tance criteria.
All environmental monitoring supplies will be growth promoted on the release date and fill date. Agar strips will be growth promoted after being exposed to the same environmental conditions as those experienced during the fill. Growth promotion will be performed for organisms required by USP Monograph for Indigenous Organisms and Anaerobes using vials/ampoules collected during the fill and upon completion of the 14‑day incubation period.
The protocol will include acceptance criteria for sterility assurance level and growth promotion.
Also included will be details of data collection, growth promotion sampling, environmental and personnel monitoring schedule, personnel movement documen­tation, incubation time and temperature, etc.

Acceptance Criteria

Upon successful completion (end‑point contamination level of not more than 0.1%) of three (3) consecutive media fills for the vial/stopper combination and ampoules, the aseptic process will be considered validated.

Related: Media Fill Validation -SVP

5.  Cross‑Contamination Control

Test Functions

1.  Verification of HVAC design, zoning of air handling units, airlocks, room pressure differentials, recirculation vs. once‑through air handling systems, room air distribution, use of HEPA filters on main return ducts to air handling plants, supply and return duct work, fresh air intakes and exhaust for buildings A, B, and C.
2.  Verification of materials and product dispersal around manufacturing facil­ity in buildings A, B, and C.
3.  Verification of spread of materials and products during maintenance and cleaning of environmental and process air handling plant and equipment.
4.  Verification of containment of materials and products during processing.
5.  Verification of dust collection system as per design.
6.  Verification of movement of personnel, gowning, and laundry as per design.
7.  Verification of utilities design, mix-up, identification, check valves, and back‑flow prevention.
8.  Verification of facility design, architectural finishes, and room layout.
9.  Verification of equipment design, construction materials, clean in‑place (CIP) units where possible, and cleaning out‑of‑place practice.
10.  Verification of cross‑contamination prevention by performing air sampling and machine swabs.
11.  Verification of prevention of cross‑contamination by cleaning system val­idation.
12.  Verification of prevention of cross‑contamination through residual analysis of finished products.
13.  Verification of pallets transfer and interlocks as per design.

Acceptance Criteria

1.  The system is installed in accordance with design specifications based on manufacturer recommendations and cGMP guidelines and documented.
2.  Materials and product dispersal around manufacturing facility in buildings A, B, and C with design specification.
3.  Spread of materials and products during maintenance and cleaning of environmental and process air handling plant and equipment is maintained and demonstrated through environmental monitoring.
4.  Containment of materials and products during processing is demonstrated through environmental monitoring.
5.  Dust collection system operates in accordance with design specifications throughout the operating range or range of intended use.
6.  General control of movement of personnel, gowning, and laundry is dem­onstrated through SOP compliance and training.
7.  General controls, alarms, identification, and interlocks operate in accor­dance with design specifications.
8.  Facility construction and architectural finishes demonstrate adherence to specifications and cGMPs.
9.  Equipment design, construction materials, CIP, and cleaning out‑of‑place practice are in compliance with cGMPs.
10.  Air sampling and machine swabs results meet the acceptance criteria estab­lished.
11.  Area/equipment cleaned in accordance with the written SOPs and meet the acceptance criteria.
12.  The pallet transfer units and interlocks operate as per design and in accor­dance with the written SOPs.

Related: Prevention of Cross - Contamination During Processing

6.  Computerized Pharmaceutical System

Test Functions

1.  Perform Installation Qualification.
2.  Confirm that hardware and software descriptions are available.
3.  Confirm that the documentation is appropriate, up‑to‑date, relevant, and complete.
4.  Verify the digital transmission inputs and outputs as appropriate.
5.  Verify analog transmission inputs and outputs as appropriate.
6.  Verify data entry and boundary testing as appropriate.
7.  Verify access control testing as appropriate.
8.  Verify SOPs for operation, maintenance, and change control.
9.  Verify training records.
10.  Verify system recovery procedure.

Acceptance Criteria

1.  The system is installed in accordance with design specifications based on manufacturer recommendations and cGMP guidelines. Instruments are calibrated, identified, and entered into the calibration program.
2.  Hardware and software systems are verified as per manual.
3.  The documentation is appropriate, up‑to‑date, relevant, and complete as per protocol.
4.  The digital transmission inputs and outputs are verified.
5.  The analog transmission inputs and outputs are verified.
6.  The data entry and boundary testing meets the specification design.
7.  The access control testing meets the specification design.
8.  SOPs are available for operation, maintenance, and change control.
9.  Training records are available.
10.  System recovery procedure is available.
Apr 22, 2012

Biocontamination Control Techniques for Purified Water System


Water treatment, storage and distribution system for preparation and distribution of purified water should have the properties to control microbiological contamination. Techniques should be employed during the qualification of water system.
•  The water systems that are operated at 70-80 °C are less susceptible to the microbial contamination then the systems operated at ambient temperature because microbes has optimum growth on ambient temperature.

Related: Reverse Osmosis Water Purification System


•  A spray ball should be used to prevent the source of contamination in head space of storage tank.

•  Vent filter should be used to avoid the contamination of the storage tank from the outer air entering into the tank. Filter should be of 0.2 μm pore size and should be validated. Vent filters should be sanitize time to time by appropriate sanitizing agents.

Related: Cleaning and Disinfection of a New Purified Water Syatem


•  Water should be continuously circulated into the distribution system to avoid the formation of biofilms i.e. the layer of the microbial population around the inner surface of the pipelines.


Related: Chemical Sanitization of RO Systems and Biofilm Removal


•  Velocity of the water flow should be considered during the validation of water system and same should be maintained during the normal operation of the water system.

•  Deadlegs should not be more then 1.5 times of the pipework diameter. It will help to avoid the stagnant water in deadlegs.
•  If water system is maintained at ambient temperature, it should be sanitize at least once in a week with hot water i.e. >70 °C or other suitable sanitizing agent. If chemical sanitizing agent is used then it should be validated for its cleaning procedure to remove from the system.

Related: Passivation of Purified Water System/ WFI System


•  Ultraviolet light should be used before the return loop to minimize the contamination entering through the water returning into the storage tank.


Also see: Guide To Inspections of High Purity Water Systems


Apr 15, 2012

Cleaning Validation Sample Protocol


CLEANING VALIDATION PROTOCOL
Product            :
Protocol No.     :
Revision No.    :
Page No….of …..

1.  Introduction

One equipment used at one stage, manufacturing of different products is very common in pharmaceuticals manufacturing. After use, the equipment is cleaned to prevent cross-contamination of drug products.
The efficacy of cleaning procedure should be such that it effectively removes traces of the previous product and detergent used.

2.  Purpose

To validate the cleaning procedure for equipments used for manufacturing is effective to remove the ingredients of previous product and detergent used to reduce the microbial contaminants.

3.  Objective

•  To establish a documented evidence of the cleaning effectiveness of the cleaning procedure to a predetermined residue level.
•  To verify that the cleaning procedure is able to clean the defined equipment consistently and reliably.

4.  Responsibilities

I.  Production Supervisor
•  To ensure that the various pieces of equipment are cleaned according to the relevant SOP. (SOP no :…….)
•  To train and monitor the operator for collecting sample by final rinse/swab of the various parts of the equipment.
II.  Head of Q.C Department
•  Responsible for validating analytical method used to analyze traces of active ingredients of the previous product and traces of detergent used.
•  To test sample according to validated analytical method
III.  Head of Microbiology Department
•  Responsible for validating analytical used to analyze and count the microbial contamination
IV.  Head of Q.A Department
•  Responsible for writing of the protocol and final report
•  To supervise the operation to ensure everything is done according to the protocol
V.  Production Manager
•  Responsible for checking of the protocol and final report
VI.  Engineering foreman
•  Responsible for supporting production personnel during cleaning validation.

5.  Procedure

A.  After completion of manufacturing of drug product, cleaning will be carried out by production personnel according to the relevant SOP. (SOP No.: …..)
B.  The production supervisor inspects the equipment visually to assure that it is clean, and fill the inspection form.
C.  For determining the active residue, the sample are taken according to the following steps:
•  Wipe off the cleaned equipment with swab test kit saturated with purified water or methanol (according to the solubility of the API of the previous product) on the critical areas.
•  Put the cotton swab into the vial and close the vial with plastic pilfer proof cap. Collected swabs should not be hold more than 24 hours under refrigeration.
•  Then send the collected sample to the Q.C department for analysis (method of analysis should be validated).
D.  For determining detergent residue, the sample are taken according to the following procedure:
•  Rinse the clean equipment with purified water
•  Collect approx. 500 ml from the final rinse into a clean amber glass bottle and close the bottle with the lid.
•  Then send the collected sample to the Q.C department for analysis (method of analysis should be validated).
E.  For determining microbial contaminants, the sample is taken according to the following procedure:
•  Open the lid of the RODAC plate.
•  Put the nutrient agar surface on the cleaned equipment at the critical area.
•  Close the RODAC plate with the lid immediately.
•  Then send the RODAC plate to the Microbiological Lab for incubation.

6.  Acceptance criteria

The following criteria are established:
•  Visual examination should not reveal any evidence of contamination. The equipment will be checked for this and will be recorded.
•  Active ingredient of the previous product: Not more than 10 ppm.
•  Samples from final rinse have purified water.
•  Conductivity of the samples: Not more than 1.3µS.
•  Microbial contaminants of the sample: Not more than 25 CFU/25 cm2

7.  Corrective action (If required)

•  If the cleaning validation results show that the equipments are below the acceptance limits or not more than the maximum detectable limit, the cleaning SOP is adequately validated.
•  A failure to meet this equipment would necessitate a review of the cleaning procedure of the residual limits. Modification in the procedure to make it more effective, or a change to more realistic limits would again necessitate three successful cleaning of the equipment before the procedure can be considered acceptable.

8.  Attachments

•  Visual inspection form
•  Surface sampling form
•  Final rinse sampling form
•  Monitoring form

9.  Protocol Prepared By:



S. No
Name
Department
Signature
Date
1.      

Quality Assurance



10.  Protocol Reviewed By:


S. No
Name
Department
Signature
Date
1.

Quality Control


2.      

Microbiology


3.      

Production


4.      

Engineering




11.  Protocol Approved By:


SI. No
Name
Department
Signature
Date
1.      

Head of Quality Assurance



Attachments:
Cleaning validation visual inspection form:
Product cleaned

Batch No.

Cleaned by

Date

Cleaning SOP No.

Date of revision

Protocol No.




No.
Equipment inspected
Result
Inspected by
Date


Clean
Not clean





















Remarks: ……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………
Reviewed By: ………………………                                            Date……………………………..
Cleaning validation surface sampling form:
Product cleaned

Batch No.

Cleaned by

Date

Cleaning SOP No.

Date of revision

Name of the equipment

Equipment No.

Protocol No.




No.
Sample type
Sample location
Sample code
Area (cm2)
Sampled By
Date
1.      
Microbiological





2.      
Microbiological





3.      
Chemical





4.      
Chemical






Remarks: ……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………
Reviewed By: ………………………                                            Date……………………………..
Cleaning validation final rinse sampling form:
Product cleaned

Batch No.

Cleaned by

Date

Cleaning SOP No.

Date of revision

Name of the equipment

Equipment No.

Protocol No.




No.
Sample type
Which Part of the equipment to be use for sampling
Sample code
Quantity
Sampled By
Date





























Remarks: ……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………
Reviewed By: ………………………                                            Date……………………………..

Cleaning validation monitoring form:
Product cleaned

Batch No.

Cleaned by

Date

Cleaning SOP No.

Date of revision

Name of the equipment

Equipment No.

Protocol No.




No.
Parameter monitored
Sample location
Result
Monitored By
Date
1.      
Detergent




2.      
Rinsing




3.      
Final rinsing




4.      
Mop




5.      
drying





Remarks: ……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………
Reviewed By: ………………………                                            Date……………………………..
Submitted By:
Md. Abdul Bake
Product Development Officer
GonoShasthaya Pharmaceuticals Limited
Bangladesh
Email - abdul.bake@yahoo.com