Cleaning Validation
The process of providing documented evidence that the cleaning methods employed within a facility consistently controls potential carryover of product (including intermediates and impurities), cleaning agents and extraneous material into subsequent product to a level, which is below predetermined levels.
Due to complexity of manufacturing and packing of multiple products using same equipment a Bracketing approach shall be applied to prioritize Cleaning Validation Program based on scientific rationale.
The approach evaluates overall cleaning requirement of the product range and concentrates the validation effort to develop Worst Case situation, where common cleaning procedures are followed for similar type (Operating Principle and Capacity) of equipment.
The Worst Case is considered on the basis of following factors:
- Physical characteristic i.e. Solubility, Cleanability
- Therapeutic Dose of the Product
- Concentration of Active Ingredient
- Equipment combination (Equipment Train)
In this bracketing approach cleaning validation of each equipment train shall be performed based upon the worst-case product selected for that equipment train.
Cleaning Validation Protocol
- Protocol Preparation and Approval Sheet
- Objective
- Scope
- Responsibility
- Validation Team
- Abbreviations and Definitions
- Cleaning Validation Approach
- Selection of Products
- Selection of Equipment’s
- Type Cleaning after every five consecutive batches of the same product
- Pre – Cleaning Validation Requirements
- Precautions and Instructions
- Acceptance Criteria -Product Residue Contamination, Cleaning agent residue contamination, Microbial Contamination.
- Cleaning Validation Programmed
- Selection of Cleaning Procedure
- Water Quality
- Selection of Analytical Method
- Analytical Method Validation
- Sampling Plan, Type of Sampling and Selection of Sampling method
- Evaluation of Cleaning Procedure
- Analytical Testing Procedure
- Cleaning Verification
- Ongoing Monitoring
- Ancillary Equipment
- Cleaning of Manufacturing Area
- Hold Time Studies
- Equipment Holding Studies Prior to Cleaning
- Cleaned Equipment Hold Time Studies
- Training
- Revalidation
- Deviations and Investigations
- Cleaning Validation Report
Objective
To evaluate the capability of cleaning procedure Type A in removing the drug residue and microbiological bio burden on equipment within established acceptance criteria, through the validation of cleaning procedures.
To establish sufficient documented evidence to assure that, cleaning procedures can repeatedly and reproducibly remove residue of the subjected product and / or cleaning agent i.e. Sodium Lauryl Sulphate (wherever applicable) – within established acceptance limit. The acceptance limit is maximum allowable quantity of product residue and / or cleaning agent, which does not affect quality and safety of the subsequent product to be manufactured, by using same equipment and facility.
To establish acceptable time limit for storage of cleaned equipment, utensils and components after cleaning (Cleaned Equipment Hold Time Study). Equipment’s are not expected to be free from all microorganisms. The objective shall be to demonstrate that there is no microbial proliferation in equipment’s during storage.
Scope
This protocol is applicable for validation of cleaning procedure to be followed in Tablet & Capsule section of Pharmaceutical Formulation Plant .
- Demonstrate that the cleaning procedure shall perform consistently according to predetermined acceptance criteria.
- No unauthorized or unrecorded modifications have been taken place.
- Cleaning validation shall be performed after Type A cleaning.
- After satisfactory visual inspection only, the equipment shall be allowed for sampling.
- Swab samples and Rinse samples shall be collected to verify the presence of active residue content and Microbiological bio burden as per given sampling plan.
- Samples should be taken from pre-defined locations as mentioned in this protocol.
- All Sampling and testing reports have been made available.
- All precautions and instructions have been followed.
- Three runs of cleaning are required to prove that the process has been validated.
Responsibility
Quality Assurance :
Responsible for ensuring the overall validation of cleaning methods, used to clean the process equipment, utensils and areas. These responsibilities for cleaning validation include:
- Preparation, Review and approval of Cleaning Validation Protocols, Reports and Cleaning Validation Summary Reports.
- The approval of SOPs, STPs, GTPs and Cleaning Method Validation Protocols & Reports.
- Execution of Cleaning Validation Activities.
- Sampling during cleaning validation.
- Handling of Deviations.
- Training of team involved in cleaning validation.
- Compile and review of Report
- Verifying the cleaning activities
Production:
Responsible for ensuring the validation of cleaning methods, followed within this department. These responsibilities for cleaning validation include:
- Review of Cleaning Validation Protocols, Reports and Cleaning Validation Summary Reports.
- The preparation and approval of general operating and cleaning procedures (SOPs).
- Execution of Cleaning Validation Activities
- Provision of personnel for the cleaning of equipment during validation studies.
- Initiation of Deviations
- Training on equipment and area cleaning SOPs.
- Checking of Cleaning activities
Quality Control :
Responsible for ensuring the validation of analytical methods used to analyze cleaning validation samples. These responsibilities for cleaning validation include:
- Preparation and Approval of Cleaning Method Validation Protocols and Reports.
- Review and Approval of Cleaning Validation Protocols, Reports and Cleaning Validation Summary Reports.
- The approval of SOPs, STPs and GTPs.
- Analysis of cleaning validation samples and report submission
- Initiation of Deviations
- Training responsibilities
Engineering :
Responsible for ensuring the
- Calculation of equipment contact surface area.
- Equipment, components, utensils and area drawings.
- Drawings and Qualification documents of supporting utilities.
Validation Team
Validation team shall comprise of the representatives from following functions:
- Quality Assurance
- Production
- Quality Control
- Engineering
Cleaning Validation Approach
This specific protocol shall be applicable to Tablet and Capsule section only.
Due to complexity of manufacturing and packing of multiple products using same equipment a Bracketing approach shall be applied to prioritize Cleaning Validation Program based on scientific rationale.
The approach evaluates overall cleaning requirement of the product range and concentrates the validation effort to develop Worst Case situation, where common cleaning procedures are followed for similar type (Operating Principle and Capacity) of equipment.
The Worst Case is considered on the basis of following factors:
- Physical characteristic i.e. Solubility, Cleanability
- Therapeutic Dose of the Product
- Concentration of Active Ingredient
- Equipment combination (Equipment Train)
In this bracketing approach cleaning validation of each equipment train shall be performed based upon the worst-case product selected for that equipment train.
A Matrix of products with the details of active ingredient, therapeutic category, strength, maximum daily dose (mg & No. of dosage units), and batch size (kg & Lacs) and solubility shall be prepared.
A Matrix of Equipment combination with the details of equipment name, I.D. No., area, capacity, contact surface area, equipment usage and preferred rinse volume for sampling shall be prepared.
On the basis of matrix of Products and Equipment’s, Worst Case situation (Product to Product Change Over) shall be derived. The rationale for each Worst Case shall be justified scientifically.
Rationale for the residue limit established should be scientific, logical and based upon knowledge of the material. The limits should be practical, achievable and verifiable.
- Type cleaning shall be done in the following situations:
- Product to Product change over
- After every five consecutive batches of the same product
- Production of same products in descending potency
- After any major changes of product contact parts
- Receiving of new equipment
Selection of Products
Product matrix and selection or worst case products) for Products manufactured
Selection of Equipment’s
Equipment matrix for equipment’s used in manufacturing
Cleaning of equipment’s that are not within the equipment train
If any equipment is not used in the production of worst case products (i.e. not covered under equipment train), effectiveness of cleaning shall be accomplished by deliberately contaminating the equipment.
Type A Cleaning after every five consecutive batches of the same product
Type A cleaning after every five consecutive batches of the same product shall be assessed by charging accelerated stability studies and results derived from Impurity profile for 5th batch & microbiological analysis data for all five batches.
Pre Cleaning Validation Requirements
The cleaning shall be done by following the SOP for cleaning of equipment.
Three successful runs of batches or different strength of the same product shall be considered for completion of cleaning validation activity.
Sampling shall be done from all the pre-decided locations and as per surface area mentioned.
The equipment’s used for manufacturing shall be as per list of equipment’s.
The critical parts of equipment, which are difficult to clean, shall be considered for sampling.
Critical in-process control shall be evaluated with respect to the laid down specification.
Swab/ Rinse samples shall be analyzed as per laid down test procedures and comply with respect to the predetermined specifications.
Pre Cleaning Validation requirements viz. Product details, Batch Numbers taken for validation, Equipments used for manufacturing & SOPs for cleaning and Approval status of applicable documents (STPs, GTPs, and Analytical Method Validation protocols & reports e.t.c.).
Precaution and Instructions
Uncleaned and cleaned equipments shall be transferred to cleaning area in closed condition. (If the cleaning is not done in the same area).
All the steps shall be followed by same sequence mentioned in the respective cleaning SOP / Cleaning validation test record.
Cleaning Agent (SLS) shall be used wherever applicable.
Visual inspection shall be performed after completion of cleaning and drying of equipments. After satisfactory observation, the equipment shall be allowed for sampling. A successful visual inspection is a pre requisite for sampling. If any residue is detected during the visual inspection, this represents a deviation which must be processed according to a pre defined procedure and the equipment shall be cleaned again until visual inspection is satisfactory.
The first step of the sampling sequence is the test for microbiological contamination to prevent false positive results from preceding tests.
The second step of the sampling sequence is the swab test.
The last step of the sampling sequence is the rinse sampling.
For cleaned equipment hold time studies the cleaned equipments must be kept completely closed (covered with cling film).
Acceptance Criteria
Product Residue Contamination
The rationale for selecting limits of carryover of product residue shall be logically based on the materials involved. The limits should be practical, achievable and verifiable. On the basis of following criteria acceptance limits i.e. Maximum Allowable Carry Over (MACO) shall be established:
Dose Criteria (or safety based criteria or medical limit criteria)
As per this criteria not more 0.001 dose of any product shall appear in the maximum daily dose of the next product
The following equation shall be used for the calculation of MACO from previous product (let be a product A to next product (let be a product B)
Maximum Allowable Carry Over (mg per batch) =TDX SF X BS /MDD
Where,
TD: Single therapeutic dose (smallest strength based on number of mg of active ingredient) of previous product (Product A)
SF: Safety Factor (0.001)
BS: Batch size of the next product (product B) i.e. Minimum Batch Size
MDD: Maximum Daily Dose; milligram of dosage units of the product B taken per day
10 ppm criteria
As per this criterion, not more than 10 ppm of any product will appear in another product.
The following equation is used to calculate the limit of product A if the next product on the production schedule is product B.
Maximum Allowable Carry Over (mg per batch) = 0.00001(mg/mg) X BS in mg
Where,
0.00001 mg of product A per 1000000mg of the product B
BS: Batch size of the next product in mg.
On the basis of dose criteria and 10 ppm criteria the MACO limit shall be calculated and the dose criteria limit shall be selected as a Worst Case condition.
After establishing MACO (with minimum value) the swab limits and / or rinse limits shall be established with respect to total product contact surface area and total rinse volume respectively.
Swab Limit (drug in mg per 100 cm2 swabbed area) =MACO X 100 /TS
Where,
100: Sampled swab area (100 cm2)
TS: Total product contact surface area (cm2)
Rinse Limit (drug in mg per liter) = MACO / Total Volume used in liters
Visual Inspection
Visual inspection shall be performed after completion of cleaning. After satisfactory observation, the equipment shall be allowed for sampling.
Cleaning Agent Residue Contamination
The rationale for selecting limits of carryover of cleaning agent (sodium lauryl sulphate) residue shall be logically based on the material involved. The limits should be practical, achievable and verifiable. On the basis of following criteria acceptance limits i.e. Maximum Allowable Carry Over (MACO) shall be established:
In case of Cleaning agent (SLS) residue, MACO shall be calculated as follows as per medical limit criteria:
No Observable Effect Level =LD50 (g/kg) X 70(kg a person) /Conversion Factor (1000)=__________
From the NOEL number a MACO can then be calculated according to
Maximum Allowable Carry Over (mg per batch) =NOEL x MBS/ SF X MDD =
Where,
LD50: LD50 value (lethal dose) of the cleaning agent i.e. Sodium lauryl sulphate
SF: Safety Factor (10000)
BS: Batch size of the next product (product B) i.e. Minimum Batch Size
MDD: Maximum Daily Dose; milligram of dosage units of the product B taken per day.
Based on the Bracketing approach the following products were selected for Worst case as per 0.001 dosage criteria and the limits shall be followed as below:
- Type of Dosage Form
- Worst case Product
- API
- Location / Area
- Limit as per Dose Criteria
- Limit as per 10 ppm Criteria
- Swab Limit
- Limit for validation -Swab Limit
- (including Recovery factor)
- Limit for validation -Rinse Limit
- Limit Of Quantification
Make the computerized report after getting swab/rinse sample Chemical and micro analysis and hold time study. Combine the rinse water sample and swab sample results and to determine the total carryover. Cleaning agent limits shall be followed as below
- Cleaning Agent
- Location/Area
- Worst case product
- API
- Next product
- MACO limit
- Rinse Limit for validation
Microbial Contamination
Swab samples shall be collected from product contact surface area immediately after completion of cleaning activities and satisfactory visual inspection. For cleaned equipment hold time studies samples shall be collected as per specified intervals (0 days, 3 days, 7 days, 10 days & 14 days). The limits for the microbiological bio burden criteria for product contact surface are presented below.
Total Aerobic Microbial Count :Swab sampling (cfu / 25 cm2)
Limit :NMT 100
During this study, identify all of the micro-organisms isolated so that the data obtained may serve as the baseline for a trend analysis program.
Once validation efforts are complete and results have established the effectiveness of the cleaning and sanitization procedures, a good microbiological control program must be implemented.
Cleaned equipment hold time studies shall be performed in one area with covering of each type of equipment.
Total Aerobic Microbial Count for manufacturing area shall be studied after completion of cleaning, by contact plate technique (Only for reference purpose only).
Cleaning Validation Programmed
Selection of Cleaning Procedure
There are following three types of cleaning methods utilized in the drug product manufacturing facilities.
Clean-In-Place (CIP)
- Cleaning of the equipment is performed in place without disassembling and transferring to the Washing area which is also defined as In Situ Cleaning.
- Cleaning process may be controlled manually or by an automated program.
Clean-Out-Of-Place (COP)
- Cleaning of disassembled equipment is performed in a central washing machine.
- The washing machine also requires validation such as the temperature, ultrasonic activity, cycle time, cleaning operation sequence, water quantity, and detergent quantity dispensed etc.
Manual Cleaning
- Difficult to clean.
- Most extensive and elaborate cleaning procedures are required.
- A high quality and extensive training program is required.
Tablet and Capsule section has designed with manual cleaning operations. Wherever, CIP or automated cleaning feature is designed for the Equipment, those methods of cleaning shall be validated in conjunction with manual cleaning.
The risk involve in manual cleaning processes is taken care of with following factors:
- Designing and Construction of washing area with segregation of used equipment cleaning with treated water, final cleaning with purified water and wiping with clean non-shredding cloth /drying with compressed air.
- Adequate protection (covering with cling film) and storage facility of cleaned equipment.
- Detailed SOPs for cleaning.
- Training/Qualification of cleaning operators.
Water Quality
Water to be used for the cleaning of manufacturing equipment is treated water (Potable water) and Purified water to be used for final rinsing of equipment.
Selection Of Analytical Method
The development and validation of analytical procedures for detection of product residue in cleaning validation sample requires the selection of appropriate analytical methods.
A specific method must be selected carefully for detection of product residue; a non-specific analytical method may lead to false analytical results.
During validation of the cleaning procedure, the analytical methods used should be able to specifically quantify concentrations of all compounds of interest that may be present in samples.
Specific method shall be employed during cleaning validation and for subsequent cleaning verification or ongoing monitoring of cleaning, non- specific methods shall be employed.
Analytical Method Validation
Any instrumental analytical procedures used to analyze cleaning validation samples need to be specified and sufficiently sensitive to determine the low levels of residues typically found in samples. The methods used to analyze samples that allow the equipment to be released for manufacture of another product shall be validated to ensure that it meets following requirements.
- Specificity
- Limit of Detection (LOD)
- Limit of Quantitation (LOQ)
- Linearity
- Precision
- Recovery of drug from spiked swabs
- Recovery of drug from spiked SS plates, Teflon sheets and other product contact materials.
- Range
- Stability of Analytical Solution
- Robustness
Sampling Plan, Type of Sampling and Selection of Sampling Method
Sampling shall be done as per sampling plan.
Samples shall be taken.
The effectiveness of cleaning procedures shall be evaluated by following methods.
- Visual Inspection: Visual inspection of equipment for cleanliness immediately before use is required by the cGMP regulations.
- Swab sampling: The area to be sampled should be selected using judgement about which areas are hard to clean.
- Rinse Sampling: Collection of rinse samples should consider hard to access locations and volume.
- Evaluation Of Cleaning Procedures
The effectiveness of cleaning procedures shall be evaluated by following sampling methods.
Visual Inspection
Visual cleanliness criteria shall be the primary criteria for the cleaning of equipment.
- Easy and preferred pre-sampling criteria
- Qualitative and subjective.
Visual inspection shall be performed after completion of cleaning. After satisfactory observation, the equipment shall be allowed for sampling.
Visual cleanliness can be evaluated by visual inspection of the equipment after cleaning as per the test record
Organoleptic techniques (i.e. visual, smell, touch) shall be used as a component of the cleaning program and additionally as one of the tests useful for the validation of the cleaning procedure.
Ensure that equipment visual inspection shall be done at a distance of less than 25 cm and lighting level should be more than 325 lux.
Swab sampling
Wet the cotton tip of swab with purified water and squeeze the cotton tip by pressing gently against the wall of test tube to remove excess of purified water.
Swab sample shall be collected from 10 x 10 cm2 (100 cm2).
Selection of sample position shall be based on difficult to clean equipment surface area.
Before collection of swab sample visual inspection of the equipment shall be done to check the cleanliness.
For cleaning validation swab sample shall be collected for chemical/ microbiological analysis from the locations specified as per the sampling locations.
Most of the equipment’s shall be swabbed for at least 5 locations, depends on equipment size, accessibility and complicity.
Strongly preferred method, as some residues may need a mechanical or physical action to remove from the surface.
Swab the surface of equipment for 100 cm2 area firmly and swab horizontally with one side of the swab and vertically with other side of the swab (10 strokes on each side).
Do not rub the surface in to & fro motion.
Put the swab into a clean tube and transfer to the quality control laboratory in a dry state,
- Pour 10 ml of sample medium (which was specified in method validation protocol) to the test tube and extract the residual drug from the swab in sample medium by sonication of the test tube for about 5 minutes.
- Take out the swab from the test solution, squeeze the cotton tip of the swab against the wall of the test tube and discard the swab. Shake the test tube to make the homogenous solution. This solution shall be used as test solution and shall be analyzed for drug swabbed, from the equipment surface.
- Sample for the microbial analysis shall be taken by microbiologist as per procedure mentioned in Protocol for validation of techniques used for bio burden analysis in cleaning validation.
Rinse Sample (Wherever applicable)
- Rinse sample shall be collected from the hard-to-access locations of the equipment’s.
- Equipment surface shall be rinsed with the given quantity of rinse volume with purified water and the sample shall be collected from the rinsate.
- After collecting the sample visually inspects the sample it shall be clear, colorless and free from particulate matter.
- This solution shall be used as test solution and shall be analyzed for the presence of the previous product .
- However results of rinse sample alone can not be used for the evaluation of cleaning validation results and its conclusion.
Samples shall be mentioned Batch Number, Name of product, Equipment Id. No, Sampling Location, Sampled by and Date. The samples shall be stored at 2-8°C up to testing.
Analytical Testing Procedure
Follow the procedure  for the analysis of cleaning validation samples to determine drug residues.
Cleaning Verification
Cleaning verification approach will be applied for the unique condition where the product being manufactured for the first time is not fitting / does not exit in the established product / equipment matrix, until cleaning procedure has been validated or it is one time activity / event the product will not be manufactured in the same manner on the commercial scale equipment.
Cleaning verification approach will be also applied while introducing/ replacing the any equipment of the train, after appropriate evaluation. Based on evaluation, verification will be performed if required for particular equipment until cleaning procedure has been validated.
Cleaning verification will establish / demonstrate the proper removal of target product residue and microbial load by which it will not alter the safety, identity, strength, purity and/ or quality of subsequent drug product being manufactured on the same equipment.
Following criteria shall be adopted:
Selection of swabbing position based on the experience for difficult to clean location of equipment or history for worst-case sampling.
Method adopted shall be qualified for the sensitivity and swab recovery.
Cleaning verification approach will be also applied while introducing/ replacing the any equipment of the train, after appropriate evaluation.
Based on evaluation, verification will be performed if required for particular equipment until cleaning procedure has been validated.
Ongoing Monitoring
Once validated, it is advisable to reconfirm cleaning effectiveness from time to time. For manual processes this is essential until sufficient data has been generated to confirm the reproducibility of the cleaning procedure.
Ongoing monitoring shall be performed with defined criteria on validation report to verify / monitor the cleaning process is able to confirm the ongoing appropriateness of the training program as well as operator ability to perform the cleaning process.
Ancillary Equipment
Ancillary equipment is utilized along with the main equipment illustrated in the equipment list. They aid in the manufacturing process in terms of product transfer. Examples of ancillary equipment are SS scoops, SS spatulas, SS beakers / measuring cylinders and SS containers etc. Cleaning validation will be established for ancillary equipment.
Cleaning of Manufacturing Area (Non contact surface area -reference purpose only)
Cleaning of manufacturing area shall be studied (for Reference purpose only) through this protocol to evaluate the area cleanliness level. The limits shall be taken as given in product contact surface area and the final conclusion shall be drawn after completion of cleaning validation.
Hold Time Studies
The objective of hold time study is for establishing time limit between equipment cleaning and reuses it to ensure that the equipment remains clean till the next use.
Equipment Holding Studies prior to cleaning
The interval between the end of production and the beginning of the cleaning process shall be established through equipment holding studies prior to cleaning.
It is important to consider the effect that weekends, holidays and delays might have on the cleaning schedule. For example, a piece of equipment that is utilized first thing in the morning may sit, contaminated with product, until the second shift starts. Having the product dry on equipment, therefore, considered as worst case.
An equipment’s shall be kept ideally for 72 hours at production area, prior to cleaning and consider as worst case.
Cleaned Equipment Hold Time Studies (Microbiological Study only)
Concerns relative to microbial control are lessened in the production of non-sterile products but are still important. Practices which minimize the potential for contamination by objectionable organism are common in the manufacture of non-sterile formulations.
To establish the expiry of cleaning in view of microbiology, equipment shall be kept ideally after cleaning for 336 hours (14 days) and microbiological swab shall be taken and analyzed at different intervals (0 hour, 36 hours, 168 hours, 240 hours and 336 hours).
This will be considering as worst case and microbial load should remain well within limit.
Training
Operator training is critical, especially for manual cleaning. During cycle development, operators should be trained in the requirements of the evolving or existing SOPs. Proper training consists of understanding the SOP, apprenticeship with qualified, trained operators and review to ensure that the training is successful. The effective training or qualification of the operators may be confirmed by monitoring of the equipment after cleaning, including, where necessary, analytical testing for residuals.
It is important not only that operator training occur, but also that the training be well documented.
Operators should be retrained each time a cleaning procedure is changed and the new training must be documents, just as in the case of a change to a manufacturing procedure.
Revalidation
The cleaning process of specified equipment for the specific product shall be revalidated in one or more of following cases
- Change of formulation procedures or quality of pharmaceutical ingredients.
- Major changes of process parameters.
- Change in facilities
- Equipment changes
- Changes in cleaning procedure
- On appearance of new findings based on current knowledge.
- Batch size change.
- Implementation of these changes shall be carried out as per change control system.
Deviations and Investigations
Any deviation observed during cleaning validation shall be recorded and investigated
If the observed deviation does not have any major impact on the validation the final conclusion shall be provided.
If the observed deviation has major impact on the validation, deviation shall be reported to the concerned department for the corrective action and validation activity shall be redone.
Cleaning Validation Report
Based on the outcome from this validation study, a report shall be prepared by Quality Assurance. The validation report shall be reviewed and then approved by all functional heads of all the concerned departments.
References
- 21 Code of Federal Regulations, parts 210 & 211
- US FDA Guide to Inspections Validation of Cleaning Process
- PIC/S Recommendations on Validation Master Plan, Installation and Operational Qualifications, Non-Sterile Process Validation & Cleaning Validation
- APIC Guide on Aspects of Cleaning Validation in Active Pharmaceutical Ingredient
- PDA Technical Report No. 29:Points to Consider for Cleaning Validation
- Ira R. Berry, Robert A. Nash, Pharmaceutical Process Validation
- Batch Manufacturing Records
- Batch Packing Records
- Analytical methods Validation Protocols & Reports
Abbreviations and Definitions
- API: ACTIVE Pharmaceutical Ingredient
- LOD: Limit of Detection
- LOQ: Limit of Quantitation
- MACO: Maximum Allowable Carry Over
- MDD: Maximum Daily Dose
- SLS: Sodium Lauryl Sulphate
- STP: Standard Test Procedure
- TD: Therapeutic Dose
- Ppm: Parts per million
- Cfu: Colony forming unit
- µg: Micro gram
- cm: Centimeter
- cm2 : Square Centimeter
- Clean: The implementation of procedures to render a piece of equipment, or a system, free of adulterants and contaminants.
- Cleaning Validation: The process of providing documented evidence that the cleaning methods employed within a facility consistently controls potential carryover of product (including intermediates and impurities), cleaning agents and extraneous material into subsequent product to a level, which is below predetermined levels.
- Contaminant: Drug active, excipient, degradant, processing aid, cleaning agent, bio burden or foreign matter that, at a high enough level remaining after cleaning may potentially contaminate the equipment surfaces or the next product.
- Dedicated Equipment/ Accessories: Equipment/Accessories only used for the manufacture of one product or one related product line.
- Equipment Train: Series of individual pieces of equipment linked together for a given process which may be cleaned individually or as a process train.
- Manual Cleaning: A cleaning procedure requiring operator performed critical steps (e.g., scrubbing with a brush or rinsing with a hose)
- Objectionable Micro-organisms: Any organisms that can cause infections, when the drug product is used as directed or any organism capable of growth in the drug product.
- Protocol: A document with agreed upon set of standards and tests.
- Rinse: To clean or treat an equipment as part of a cleaning procedure.
- Swab: An absorptive device used to remove a sample from a surface.
- Visually Clean: Absence of visible contaminants.
- Worst case: Worst case is those conditions within normal parameters most likely to give failure.
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