SOP for Cleaning Validation
This Document describes (Standard Operating procedure) SOP for carry out the Cleaning Validation of equipment used in the manufacturing of Pharmaceutical Products.
SOP for Cleaning Validation
I. Purpose & Scope:
- The purpose of this SOP for carry out the Cleaning Validation of equipment used in the manufacturing of Pharmaceutical Products
- This Standard operating procedure shall be applicable for cleaning validation required for cleaning of all equipment’s which are in contact with product
II. Responsibilities:
- All Production, engineering, Quality Assurance personnel shall be responsible to follow and implement this SOP.
III : Introduction and Procedural Part :
Procedure:
Cleaning of equipment used in the manufacturing of Pharmaceutical Product is necessary to avoid cross contamination of Active Ingredients and various excipients from previous products. It also prevents contamination form lubricants used for equipment, machinery & cleaning agents if any and cleaning tools such as brushes mops etc. during cleaning operation. It also established bio-burden of the equipment. This cleaning procedure shall be validated.
Types of Cleaning:
Batch to Batch Cleaning (Type A cleaning):
- This cleaning process aims the level of cleaning the equipment to remove gross accumulation of previous product residues and ensure that the equipment is free from any obvious residues. It is applicable in any of the following conditions:
- Between batches of the same product and strength provided color\odor\flavor is same, this cleaning is mandatory in between two batches.
- Between batches of the same product and ascending potency provided color\odor\flavor is same, this cleaning is mandatory in between two batches.
- At the end of the day/ operation.
Product to Product Cleaning (Type B cleaning):
This procedure is applicable in any of the following condition.
- Product changeover and after manufacturing of campaign batches.
- Products with descending potency of active ingredient/different color\odor\flavor in case of drug products.
- When equipment has crossed the dirty equipment hold time, Type A cleaning is not adequate even if there is no product change over. Hence type B cleaning has to be performed.
- Equipment has crossed the clean equipment hold time period, Type B cleaning should be performed before the next batch.
- Cleaning of new equipment or Equipment after relocation.
- After any maintenance work (breakdown or preventive)
Selection of cleaning method:
- Manual cleaning, semiautomatic procedure, automatic procedure, CIP (Clean-in-place) COP (Clean-out-of-place)
- Manual Clean-In-Place method: Cleaning of equipment shall be performed in place without disassembling and transferring to washing area.
- Manual Clean-Out-of–place (MCOP) Method: Cleaning of disassembled Equipment /Parts/ accessories, in a designated washing area.
- Product manufactured by using dedicated equipments or production areas considered for campaign cleaning.
Cleaning Agent:
Detergent should facilitate the cleaning process and be easily removable, potential impact on material, possible degradation of the solvent. Acceptable limit for detergent residues after cleaning should be defined. Few solvents listed below:
- Aqueous cleaning-Water
- Organic solvent-IPA
- Water surfactant-SLS (Sodium lauryl sulphate)
Campaign Manufacturing:
The number of lots of the same product manufacture, campaign manufacturer of products eg. Determination of max. campaign length for intermediate or through cleaning.
Cleaning Validation:
- Cleaning validation is the methodology used to assure that a cleaning process removes residues of the Active Pharmaceutical Ingredients of the product manufactured in a chain of equipment, the cleaning aids utilized in the product manufactured in a chain of equipment, the cleaning aids utilized in the cleaning process and the microbial attributes. All residues are removed to predetermined levels to ensure the quality of the next product manufactured is not compromised by residue contamination from the previous product.
- For the purpose of cleaning, product matrix has been prepared using Product Name, Generic Name, Active Pharmaceutical Ingredient (API), strength manufactured product, solubility of related API, Toxicity and Potency & Total contact surface area and on the basis of the same total surface area has been calculated.
- A matrix should be prepared to select worst case product for maximum allowable carry over (MACO) on the basis of previous product- API, next product, batch size in kg, Largest recommended Daily Dose, Total surface area, swab area, Cleanability of hard to clean area, solubility, Toxicity based on HBEL level, NOAEL calculation based on the highest tested dose at which no “critical” effect is observed, PDE calculation etc.
The worst case considered based on the following Criteria.
- MACO Value calculated considering dose and PDE Criteria for all the product irrespectively of solubility.
- Solubility (If two products have similar lower MACO but different solubility).
- Concentration of active materials in dosage form
- Difficult to clean product nature
- In product containing more than one API, the worst is identified based on least solubility in water and lower MACO Value and if two or more API has the same solubility then API which has lower MACO Value amongst shall be considered during cleaning validation study.
- In the matrix of multiple products, if two products have different solubility (A : Insoluble ,B :Soluble) and same MACO (lower) value then product with least solubility and lower MACO value(i.e. Product A) shall be selected as worst case.
- In the matrix of multiple products, if one product (A) is higher solubility and lower MACO and other product B has less solubility and MACO is second lowest value of all products then worst case will be product B and MACO will be considering of product A.
- Dedicated equipment or production areas, Cleaning (Manually or Automated cleaning), campaign maximum length product manufacturing and intermediate cleaning while operation.
- Cleaning agent (easily removable, potential impact on material, degradation of the solvent) residue limit (water used in cleaning operations)
- Worst case product shall be shortlisted through Product matrix having lowest PDE Value and defined criteria as identified during worst case selection
Hardest to Clean out – Experience from Production:
- Experience from production with regard to how difficult a substance is to clean out. Hard-to-clean substances are identified and the difficulty of cleaning could be rated according to the three categories suggested below.
Category: 1 = Easy, 2 = Medium, 3 = Difficult
- Solubility: A solubility-rating should be carried out based on the solubilities of the substances in the solvents used for cleaning.
| Group | Included descriptive terms | Approximate quantities of solvent by volume for 1 part of solute by weight |
| 1 | Very soluble
Freely soluble |
less than 1 part
from 1 to 10 parts |
| 2 | Soluble
Sparingly soluble |
from 10 to 30 parts
from 30 to 100 parts |
| 3 | Slightly soluble
Very slightly soluble Practically insoluble Insoluble |
from 100 to 1 000 parts
from 1 000 to 10 000 parts more than 10 000 parts – |
- Determination of a PDE involves Hazard identification by reviewing all relevant, identification of critical effects, determination of the no-observed-adverse-effect level (NOAEL) and use of several adjustment factors
- Hazard Identification: For hazard identification, a review of all available animal and human data should be performed for each compound. Data for hazard identification would include non-clinical pharmacodynamic data, repeat-dose toxicity studies, carcinogenicity studies, in vitro and in vivo genotoxicity studies, reproductive and developmental toxicity studies as well as clinical data (therapeutic and adverse effects).
In order to identify the most relevant hazards related to a specific compound, the following steps shall be followed. A comprehensive review of readily available animal and human data. The data set will differ depending upon whether the drug is a novel compound in development, a proprietary drug in commercial production, or a generic drug.
The following references should be evaluated and obtained specific to the substance of interest or the class of drug substances:
- General toxicology and pharmacology references
- Medical and toxicology subscription data base and web sites
- Drug innovators website or Drug Innovators Clinical Investigator brochure or toxicology summary for a research Compound
- National Library of Medicine literature search engines
- National Drug Agency websites
- Once all the literature has been assembled, it should be carefully reviewed.
- This review may lead to the discovery of additional relevant references to be retrieved and reviewed as well.
- If data set is incomplete, the identified gaps will critically assess with regards to the impact on health based exposure limit.
Identification of critical effects:
Critical effects include most sensitive indicator of an adverse effect seen in non-clinical toxicity studies e.g. from mechanistic studies, pharmacodynamic data etc. Critical effects also include any clinical therapeutic and adverse effect.
- Established no-observed-adverse-effect level [NOAEL(s)]: For all critical effects identified, a NOAEL should be established. The NOAEL is the highest tested dose at which no “critical” effect is observed. If the critical effect is observed in several animal studies, the NOAEL occurring at the lowest dose should be used for calculation of the PDE value. If no NOAEL is obtained, the lowest-observed-adverse-effect level (LOAEL) may be used. A NOAEL based on clinical pharmacodynamic effects should correspond to the highest dose tested which is considered therapeutically inefficacious.
Application of adjustment factors:
The PDE is derived by dividing the NOAEL for the critical effect by various adjustment factors (also referred to as safety-, uncertainty-, assessment- or modifying factors). F1 to F5 are addressing the following sources of uncertainty:
F1: A factor (values between 2 and 12) to account for extrapolation between species
F2: A factor of 10 to account for variability between individuals
F3: A factor 10 to account for repeat-dose toxicity studies of short duration, i.e., less than 4-weeks
F4: A factor (1-10) that may be applied in cases of severe toxicity, e.g. non-Genotoxic carcinogenicity, neurotoxicity or teratogenicity
F5: A variable factor that may be applied if the no-effect level was not established. When only an LOAEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.
- Selection of final PDE: Calculation of PDE value and lowest PDE value shall be used
- Risk assessment shall perform on introduction of new product within the manufacturing facility as per format “risk assessment for new product”.
Calculate the maximum allowable carry over (MACO) of active ingredient in mg per swab by following the equation given below, if swab sampling is to be done.
-
NOAEL Calculation:
It is calculated as follows,
NOAEL= (*highest/ Lowest dose at which no “critical” effect is observed ×70kg)
2000
Where,
*Highest/ Lowest dose at which no “critical” effect is observed-A highest tested dose at which no “critical” effect is observed. If the critical effect is observed in several animal studies, the NOAEL occurring at the lowest dose should be used for calculation of the PDE value. If no NOAEL is obtained, the lowest-observed-adverse-effect level (LOAEL) may be used.
70kg – Average adult weight and
2000 – Constant
-
PDE Calculation
NOAEL x Weight Adjustment
PDE= ————————————————-
F1 x F2 x F3 x F4 x F5
Where
F1: A factor (values between 2 and 12) to account for extrapolation between species
F2: A factor of 10 to account for variability between individuals
F3: A factor 10 to account for repeat-dose toxicity studies of short duration, i.e., less than 4-weeks
F4: A factor (1-10) that may be applied in cases of severe toxicity, e.g. non-Genotoxic carcinogenicity, neurotoxicity or teratogenicity
F5: A variable factor that may be applied if the no-effect level was not established. When only an LOAEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.
F1: (SPECIES EXTRAPOLATION FACTOR)
| Value | From (Animal) | To (Human) |
| 5 | Rat | Human |
| 12 | Mice | |
| 2 | Dogs | |
| 2.5 | Rabbits | |
| 3 | Monkeys | |
| 10 | Other animals |
F2: Individual variability factor:
A factor of 10 to account for variability between individuals. 10 are used consistently, by default, 10 to be entered at the place of F2 in the equation.
F3: Repeat dose toxicity study factor:
- A factor 10 to account for repeat dose toxicity studies for short duration, i.e. less than 4 weeks.
- Lesser duration – Higher the factor value, longer duration – Lower the factor value.
- Factor value varies from 1 to 10.
F4: Severe Toxicity study factor:
- The factor that may be applied in case of severe toxicity
- Toxicities like non-Genotoxic, carcinogenicity, neurotoxicity or teratogenicity come under sever toxicity.
- Factor value varies from 1 to 10 depending on the level of reproductive toxicity is associated with or without maternal toxicity.
Values of Repeat Dose Toxicity Study
| Value | Study duration in rodents (i.e. Rats, Mice & Mouse) | Study duration in non-rodents (i.e. Rabbits, cats, dogs, monkeys) |
| 1 | 1 year (also in Rabbits) | 7 years |
| 2 | 6 months | 3.5 years |
| 5 | 3 months | 2 years |
| 10 | For shorter duration i.e. less than 4 weeks | |
| 1 | Reproductive study in which whole period of organogenesis is covered | |
Values of Severe Toxicity
| Value | Reproductive toxicity condition |
| 1 | Fetal toxicity associated with Maternal toxicity |
| 5 | Fetal toxicity without Maternal toxicity |
| 5 | Teratogenicity with Maternal toxicity |
| 10 | Teratogenicity without Maternal toxicity |
F5: Database incompleteness factor (Availability of NOAEL or LOAEL):
- This factor may be applied in the No Observed Adverse Effect Level (NOAEL value is absent) was not established.
- When only LOEL (Lowest Observable Effect Level) is available, factor value shall be 10.
- Severity of the toxicity should be considered while assigning factor value
-
MACO Calculation
MACO/swab = PDE x [MBS (B) in mg] x [Swab Area]
[LRDD (B) in mg] x [shared equipment surface area between products]
Where,
| B | = | Next Product to be manufactured (B) |
| PDE | = | Permitted Daily Exposure |
| LRDD (B) | = | Largest recommended Daily Dose of Product ‘B’ in ‘mg’. |
| MBS (B) | = | Minimum Batch Size of Product ‘B’ in ‘mg’ |
- Calculate the maximum allowable carry over (MACO) of active ingredient in next product is calculated by following equation
MACO = PDE x [MBS (B) in mg]
[LRDD (B) in mg]
Where,
| B | = | Next Product to be manufactured (B) |
| PDE | = | Permitted Daily Exposure |
| LRDD (B) | = | Largest recommended Daily Dose of Product ‘B’ in ‘mg’. |
| MBS (B) | = | Minimum Batch Size of Product ‘B’ in ‘mg’ |
MACO (one equ. in mg) = [MACO for total equip.] x [Equip. surface area]
Total equip. product contact shared surface area
MACO (mcg/ml) = [MACO value for equip.] x 1000
Rinse volume used for equipment in ml
Microbial Contamination:
In-house limits (stringent) for swab method:
- Total bacterial count : Not more than 100 cfu / swab
- Total fungal count : Not more than 10 cfu / swab
Hold time Study:
- For establishing time limit between equipment cleaning and reuse is to ensure that the equipment remains clean till the next use. This needs demonstration that there is no microbial proliferation in cleaned equipment during storage.
Cleaned Equipment Hold Time Study (CEHT):
- Hold time study shall be carried out to ensure the suitability of cleaned equipment, stored in its prescribed storage condition and does not increase the Microbial contamination level is not more than the limit of freshly cleaned equipment. In case of re-validation due to change in worst case, a risk assessment to be performed to conclude on any requirement for revalidation of microbial study.
- Cleaned Equipment Hold time study shall be carried out for Critical Process Equipment e.g. RMG, Compression etc.
- Incase more than one equipment has same MOC & DESIGN with different capacity, the equipment with preferably higher capacity with worse case, molecules shall be selected for CEHT Study.
Procedure for CEHT Study, where water is used as cleaning agent:
- Collect the initial swab sample of surface (Product contact surface only) for microbial evaluation after cleaning of equipment (Day-1).
- Periodically sample the Product contact surface at an interval as defined in the respective protocol.
- Identified the location of swab sampling as defined in the protocol.
- Send the swab sample to Microbial lab along with test request slip.
- Based on the result, determined the maximum number of days equipment can be kept after cleaning.
Procedure for CEHT Study, where cleaning agent other than water:
After cleaning of the equipment as per relevant procedure, swab sample shall be taken for chemical analysis to ensure the residue of previous product / possible contamination due to HVAC /storage condition shall not impact on Cleaned equipment within its established storage condition. The CEHT study shall be performed based on the protocol.
Dirty Equipment Hold Time Study (DEHT):
- The dirty equipment hold time studies shall be carried out to determine the microbial proliferation over a period of time and whether the same can be removed, applying the cleaning procedure referred in SOP to the level prescribed for cleaning equipment. In case of re-validation due to change in worst case, a risk assessment to be performed to conclude on any requirement for revalidation of microbial study.
- Dirty equipment Hold time study shall be carried out for Critical Process Equipment e.g. RMG, Compression etc.
- In case where more than one equipment has same MOC & DESIGN with different capacity, the equipment with higher capacity of equipment for worse case product (Preferable wet granulation product) shall be selected for DEHT Study
Procedure for DEHT Study :
- Collect the initial swab sample of surface (Product contact surface only) for microbial test after completion of process in the equipment.
- Periodically sample the Product contact surface for microbiological proliferation at an interval as defined in the protocol (maximum use during campaign batches).
- Identified the location of swab sampling as defined in the protocol.
- Send the swab sample to Microbial lab along with test request slip.
- After collection of sample as defined in protocol, clean the equipment and collect the sample for Microbial analysis.
- Based on the result, determined the maximum number of days the equipment can be kept without cleaning after use.
- Hold time study protocol shall be prepared, reviewed and approved by QA. The hold time study report shall be summarized after satisfactory completion of the study. The supporting data shall be attached with report.
- The product shall be prepared for the study with following content (but not limited to)
- Approval
- Objective
- Scope
- Responsibility
- Equipment & Product details
- Cleaning and Analysis methods
- Sampling Plan
- Acceptance Criteria
- Result Reporting
- Conclusion
- Summary
SAMPLING PROCEDURE:
Visual Inspection:
After cleaning of the equipment visual inspection shall be done. No product residue should be visible to naked eyes when the surface is inspected from a distance of about 1 foot (if more then closest possible distance).
Swab Sample for Chemical analysis:
- After visual inspection, swab sampling shall be carried out from identified ‘Hard to Clean’. The swab shall be wet in purified water. Swab samples from different areas of equipment shall be collected. Swab area shall be measured for swabbing. Swab is approx 5 x5 cm (25cm2) areas as per the Figure A & B.
- The first side of swab is swiped horizontally over the template opening, then the swab is flipped over and the second size is swiped vertically over the same surface by applying uniform pressure to ensure that all the residual materials are extracted with the swab. Swabbing shall be done using 5 to 7 parallel horizontal strokes and 5 to 7 parallel vertical strokes in the marked area assuring that the entire area is swabbed.
- After swabbing, each sample shall be placed inside the stoppered test tube duly labeled and submitted for analytical testing.
- Take swab samples from more than one item to cover 05 x 05 Sq.cm areas, if the area of item is less than 05 x 05 Sq.cm.
- Swab sampling shall be carried out. For microbiological testing sterile cotton swab shall be used for swabbing. Take sterilized swab and test tube containing pre sterilized diluents 10ml 0.9% saline/buffered peptone water for each sampling points.
- Swab samples from different areas (these areas shall not be same as that used for chemical testing) shall be collected. Aseptically the sterile swab its packing, moisten it with sterile diluents. Aseptically carry the swab of 5 x5 cm (25cm2) to the sampling sites. Swabbing shall be done using parallel horizontal stroke overlap with vertical strokes in marked area. After swabbing each swab sample shall be placed inside a properly labeled sterile test tube. Each swab sample shall then be analyzed for Total bacterial count, Total Fungal count.
Rinse sample for Chemical analysis:
After swab sampling, the equipment shall be rinsed with approx. 1000 ml volume of purified water.
- Rinse sample shall be collected in the bottles.
- After the collection of rinse sample, (stopper) close the bottle and label it for identification of rinse sample.
- Send the rinse sample bottle to Quality Control Laboratory for analysis.
Criteria for Validation /Revalidation strategies:
Cleaning validation shall be repeated
- At the time of inclusion of new product if found as new Worst Case.
- In case of change /modification of any equipment
- In case of Change of Cleaning procedure/solvent
- In case of failure (OOS) observed in regular sample analysis
- Every after 5 years
Cleaning Validation Protocol:
- Cleaning Validation protocol shall be written and approved by the Responsible person, before starting the validation work. Prepare the cleaning validation protocol as per the guidelines.
- Numbering system of Protocol :
- Cleaning Validation protocol shall consists of 10 characters:
- First 2 characters denotes the Quality assurance department like QA 3th character is slash “/”. 4th 5th and 6th characters are “CVP”, denotes Cleaning Validation protocol 7th character is slash “/”. Next three characters are numerical like 001,002 etc., denotes the serial Number. Next character is slash “/”. Last two characters are numerical denotes revision number as 00, 01 etc.
- eg.QA/CVP/001/00 – First Cleaning Validation protocol of product 00.
- Numbering system of Report:
- Cleaning Validation protocol shall consists of 10 characters:
- First 2 characters denotes the Quality assurance department like QA, 3rd character is slash “/”. 4th 5th and 6th characters are “CVR”, denotes Cleaning Validation Report 7th character is slash “/”. Next three characters are numerical like 001,002 etc., denotes the serial Number. Next character is slash “/”. Last two characters are numerical denotes revision number as 00, 01 etc.
- eg.QA/CVR/001/00 – First Cleaning Validation Report of product 01
Content of cleaning Validation Protocol:
- Protocol approval sheet.
- The protocol shall be prepared by QA, reviewed by QC, Production, Engineering and QA. Same shall be approved by QA head.
- Protocol revision history
- Abbreviation
- Objective: (The objective of this cleaning validation is to lay down a document and to outline the cleaning validation program. Cleaning Validation will ensure cGMP compliance of cleaning procedure and limits.
- Scope: (Evaluation of overall cleaning validation process).
- Responsibilities:
- Re-validation criteria
- Process flow chart
- Validation study design (Product details, API solubility details, Selection of product for cleaning validation)
- Process chain
- Equipment details
- Reference procedures
- Scientific approach to establish cleaning validation acceptance criteria (PDE criteria)
- Sampling procedure
- Analytical testing of cleaning validation study
- Change Control/Deviation/Out Of Specification/CAPA Detail
- Summary and conclusion
- Analytical method validation performed as per respective SOP
- Any non-conformity/failure results observed during cleaning validation shall be handled through deviation procedure for investigation, impact assessment of other batches, CAPA and closure
IV : Annexure:
| Annexure No | Format Name |
| Annexure-I | Cleaning validation protocol |
| Annexure-II | Risk Assessment for new product |
ANNEXURE – I
Page No.: X of Y
| CLEANING VALIDATION PROTOCOL | Page X of Y | |||||
| Document no. | : | Version no. | Effective date | |||
INDEX
| Sr.No. | Title | Page no. |
PROTOCOL APPROVAL SHEET:
Validation Protocol Preparation details:
| Department | Name | Designation | Sign and date |
| Quality Assurance |
Validation Protocol Review details:
| Department | Name | Designation | Sign and Date |
| Production | |||
| Quality Control | |||
| Engineering | |||
| QA |
Validation Protocol Approval details:
| Department | Name | Designation | Signature |
| Quality Assurance |
|
|
- Protocol revision history:
| Version No. | Details of Revision | Reason for Revision |
- Abbreviations
- Objective:
- Scope:
- Responsibility:
- Re-validation criteria:
- Process flow chart
- Validation study design:
- Scientific approach to establish cleaning validation acceptance criteria
- Sampling procedure:
- Analytical testing of cleaning validation studies:
- Change control/deviation/out of specification/CAPA detail
- Summary and conclusion
ANNEXURE – II
Page No.: X of Y
| RISK ASSESSMENT FOR NEW PRODUCT | Page X of Y |
| Product Details | |||||||||||||||||||||||||||||||||||||||||||||
| Product Name |
|
||||||||||||||||||||||||||||||||||||||||||||
| Generic Name |
|
||||||||||||||||||||||||||||||||||||||||||||
| Strength |
|
||||||||||||||||||||||||||||||||||||||||||||
| Category |
|
||||||||||||||||||||||||||||||||||||||||||||
| Active Pharmaceutical Ingredient (API) | |||||||||||||||||||||||||||||||||||||||||||||
| Name of Active Pharmaceutical Ingredient (API) | |||||||||||||||||||||||||||||||||||||||||||||
| Solubility of active pharmaceutical ingredients (API) |
|
||||||||||||||||||||||||||||||||||||||||||||
| TOXICITY (Health Based Exposure Limits (HBEL)
|
Highly hazardous products are identified based on their inherent toxicological and pharmacological characteristics that may cause adverse effects at low doses by other mechanisms
1. Genotoxic (specifically mutagenic) compounds that are known to be, or highly likely to be, carcinogenic to humans. 2. Compounds that can produce reproductive and/or developmental effects at low dosages, for example where evidence exists of such effects being caused by a clinical dose of <10 mg/day or dosages in animal studies of ≤1 mg/kg/day. 3. Compounds that can produce serious target organ toxicity or other significant adverse effects at low doses, for example where evidence exists of such effects being caused by a clinical dose of <10 mg/day or dosages in animal studies of ≤1 mg/kg/day 4. Compounds with a high pharmacological potency i.e. recommended daily dose of <1 mg 5. Compounds with a high sensitizing potential.
A. NOAEL Calculation: The NOAEL is the highest/ Lowest tested dose at which no “critical” effect is observed. If the critical effect is observed in several animal studies, the NOAEL occurring at the lowest dose should be used for calculation of the PDE value. If no NOAEL is obtained, the lowest-observed-adverse-effect level (LOAEL) may be used.. It is calculated by using formula, NOAEL= (highest / Lowest dose at which no “critical” effect is observed ×70kg) 2000
= (________×70kg) = __________ 2000
Where, 70kg-Average adult weight and 2000-constant
B. PDE Calculation NOAEL x Weight Adjustment PDE= ————————————- F1 x F2 x F3 x F4 x F5 Where F1: A factor (values between 2 and 12) to account for extrapolation between species. F2: A factor of 10 to account for variability between individuals F3: A factor 10 to account for repeat-dose toxicity studies of short duration, i.e., less than 4-weeks. F4: A factor (1-10) that may be applied in cases of severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity F5: A variable factor that may be applied if the no-effect level was not established. When only an LOEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.
Ø F1: (Species Extrapolation Factor)
Ø F2: Individual variability factor: A factor of 10 to account for variability between individuals. 10 are used consistently, by default, 10 to be entered at the place of F2 in the equation. Ø F3: Repeat dose toxicity study factor: · A factor 10 to account for repeat dose toxicity studies for short duration, i.e. less than 4 weeks. · Lesser duration – Higher the factor value, longer duration – Lower the factor value. · Factor value varies from 1 to 10. Ø F4: Severe Toxicity study factor: · The factor that may be applied in case of severe toxicity · Toxicities like non-genotoxic, carcinogenicity, neurotoxicity or teratogenicity come under sever toxicity. · Factor value varies from 1 to 10 depending on the level of reproductive toxicity is associated with or without maternal toxicity.
Values Of Repeat Dose Toxicity Study
Values Of Severe Toxicity
Ø F5: Database incompleteness factor (Availability of NOAEL or LOAEL): · This factor may be applied in the No Observed Adverse Effect Level (NOAEL value is absent) was not established. · When only LOAEL (Lowest Observable adverse Effect Level) is available, factor value shall be 10. · Severity of the toxicity should be considered while assigning factor value
Calculation: __________ x ____________ PDE= —————————————————— _____ x_____ x ____ x ______ x _____
PDE= ________________________
|
||||||||||||||||||||||||||||||||||||||||||||
| Maximum allowable carry over (MACO) calculation | Maximum allowable carry over (MACO), limit for swab shall be calculated based on the, maximum daily dose of next product and minimum batch size of next product to identify the worst case product. The rinse limit shall be calculated based on rinse volume used for equipment.
The MACO and limits shall be calculated as below:
MACO = PDE x [MBS (B) in mg] x [Swab Area] [LRDD (B) in mg] x [shared equipment surface area between products] Where, B= Next Product to be manufactured (B) PDE= Permitted Daily Exposure LRDD (B)= Largest recommended Daily Dose of Product ‘B’ in ‘mg’. MBS (B) = Minimum Batch Size of Product ‘B’ in ‘mg’ MACO: Maximum Allowable Carry Over
Calculation:
________ x ________ x _______ MACO = ————————————————- = ———————- _________ ×______________ |
||||||||||||||||||||||||||||||||||||||||||||
| Cleanability
|
|
||||||||||||||||||||||||||||||||||||||||||||
| Process chain |
|
||||||||||||||||||||||||||||||||||||||||||||
| Equipment Details: |
|
||||||||||||||||||||||||||||||||||||||||||||
| Summary of Risk Assessment for new product |
|
||||||||||||||||||||||||||||||||||||||||||||
| Other approach (if any) |
|
||||||||||||||||||||||||||||||||||||||||||||
| Conclusion |
|
||||||||||||||||||||||||||||||||||||||||||||
Note: During execution of the risk assessment for new product above criteria shall be vary depending on the product registered market. It shall be changed, added as per regulatory requirement.
| Prepared By | Checked By | Approved By | |
| Sign and date | |||
| Name | |||
| Designation |
