To Describe a Procedure for execution of Cleaning Validation Study.
This SOP is applicable for execution of Cleaning Validation Study.
|Executive/Designee of QA, QC, Production, Store and Maintenance||Preparation of Cleaning Validation Protocol and Execution of Cleaning Validation Study.|
|Executive QA/Designee||Issuance of validation protocol. Recording the deviations happened during validation. Maintaining the records of validation.|
|Department Heads of QC, QA, Store, Production and Maintenance||Implementation of SOP and Cleaning Validation criteria.|
|Head Quality Assurance||Compliance with SOP and Implementation of Cleaning Validation Protocol and Report.|
- 4. Procedure
- Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing of medicinal products.
- During the preparation of cleaning procedure and its validation and especially during determination of acceptability limits, the following issues shall be taken in consideration
- Purpose of equipment
- Equipment design
- Type of contaminant
- Assessment of GMP relevance
- 4.1 General concept
- Three consecutive validations will be performed to prove that the method is validated.
- Whenever a new product is introduced, equipment usage and nature of potential contaminant will be studied to assess whether it poses a challenging study for cleaning validation.
- If the new product represents worst case, study/ identify/develop method of cleaning to be employed. Simultaneously develop Analytical method for cleaning and validate the same.
- Revalidation Policy.
- 4.2 Types of Contaminants
- The selection of the method of cleaning depends primarily on the characteristic of contaminant or material that has to be removed from the equipment during cleaning process.
- Residual contaminants after cleaning may be:
i. Chemical – residues of the previous product.
ii. Biological – microorganisms
iii. Physical – particulate matter.
4.3 Level of cleaning:
Levels of cleaning during processing depends on:
Equipment usage (e.g. dedicated or not)
Stages of manufacturing
Nature of contaminant (e.g. solubility, toxicity, color etc.)
Our policy is to carry out cleaning after the end of each process, so that the equipment is clean and ready for the next use.
Elements of cleaning validation:
Cleaning validation study includes:
4.4 Qualification of the Cleaning Procedure
Cleaning validation is performed according to the plan and activities described in the Qualification Protocol. In order to initiate cleaning validation, the following prerequisites should be met:
- Defined, published cleaning procedures, approved by Quality Assurance.
- Defined and validated methods of analysis.
- Defined sampling.
- Trained employees.
4.5 Cleaning Procedures
A. For each equipment there should be a defined and detained SOP, which states the cleaning agents, accessories to be used and cleaning procedures.
Identification of equipment
Characterization of products
Determination of cleaning agents
Analytical method and its validation
Establishment of acceptance criteria
B. Identification of Equipments:
Identify equipments to be cleaned.
Identify difficult to clean areas
Check for ease of dismantling
C. Characterization of products:
Study activity/toxicity, solubility of the active substance of current batch and dosage and batch size of next product to be taken on the equipment.
D. Determination of Cleaning Agents:
Identify cleaning agents to be used
Identify number of cleaning cycles
Identify equipments / materials to be used for cleaning.
Based on above, prepare detailed written cleaning procedures for each equipment.
E. Analytical Methods and its validation:
In order for the analytical testing of the cleaning validation samples to yield meaningful results, the analytical methods used should be validated.
Analytical method validation for cleaning should include limit of detection, limit of quantification, acceptance criteria and rationale for setting the specified limits.
F. Sampling Procedure:
Sampling plan for validation study should be drawn which includes:
Sampling technique: Type of Sampling methods to be used are,
Direct surface sampling by swab.
Rinse water sampling (for equipment cleaning).
Plate exposure (for area cleaning).
Two easy to clean and two hard to clean areas should be clearly defined in Protocol.
G. Sampling Procedure:
Should mention how many samples are to be taken
- Swab samples should be taken separately for chemical and microbiological studies
- For each of chemical and microbiological analysis take 2 swabs from easy to clean hard to clean locations.
- How the samples are to be taken.
- H. Sample Numbering:
Swab samples should be numbered numerically and sequentially like 01, 02 etc for identification.
I. Establishment of Acceptance Criteria:
Based on the data available calculate acceptance criteria for both Pharmacological dose method and limiting the level of product to 10 ppm which appear in the following product.
Of these two, choose the criterion with stringent limits and detectable by analytical method.
Microbiological limit is 50 CFU/100 CM2. Per swab
J. Validation Protocol
Validation protocol defines protocol number.
Protocol defines a validation team that will be responsible for carrying out validation studies. Validation team comprises of at least one responsible person from production, QC & QA department.
Responsibilities of team member are:-
Production – Carrying out cleaning methods & implementing validation protocol.
Quality Control – Developing analytical method for cleaning, sampling, testing & recording the results.
Quality Assurance – Issuing & reviewing of protocol, supervision of validation activities.
- Validation protocol given details location, product manufactured, profile of active ingredient, cleaning agents used, testing equipment to be used, sampling points, sampling procedures, limit of detection acceptance calculation, surface area, validation report etc.
- Responsible persons from Production, QC and QA should formally approve the cleaning validation protocol.
- After approval Validation protocol is issued to QC Department.
- QC will perform validation studies in accordance with protocol and record results in validation report.
- K. Validation Procedure:
- After completion of the manufacturing process, workman will clean the equipment.
- If the cleaned equipment is listed in the protocol, production person will inform QC Department to collect samples for testing and QA department for supervision.
- QA/QC chemist will first check visually for cleanliness of equipment.
- If it observed not clean, instruct for re-cleaning.
- If it observed visually cleaned, collect samples separately for both chemical and microbial analysis (if required) from locations given in the protocol as per sampling procedure.
- Samples are carried to QC, where testing of the samples will be done using validated Analytical method.
- L. Validation Report:
- QC will record the results of testing in the protocol.
- QC will return the protocol with documented results and attachments like work sheet, graphs, chromatograms etc. to QA for review.
- After completion of documented studies, QA will write conclusions regarding acceptability of the results and status of procedures considered for validation.
- Any recommendations based on the documented results will be mentioned.
- References to the procedures used for cleaning, sampling and testing should be mentioned in the validation report.
- All the members of validation team should approve conclusion
- In cases where it is unlikely that further batches of the product will be manufactured for a period of time, it is advisable to generate interim reports on batch-to-batch basis till such time the cleaning validation study is complete.
- If the results of validation of any of the three studies are non-conforming to set limits of acceptance criteria, QC should inform immediately to QA.
- Further manufacturing process on the equipment/in the area should be suspended.
- Re-validation should be performed.
- Prior to re-validation, cleaning methods/procedures, sampling methods/ procedures and analytical procedures employed should be re-checked and reviewed.
- M. Re-validation Policy:
- Revalidation of validated cleaning procedures will be considered –
- Once in a year, three replicate studies will be performed.
- In case of changes in equipment/process of product
- If the new product represents worst-case challenge.
- N. The common factors should be taken into consideration when defining cleaning procedures:
i. Physical and chemical characteristics of contaminants (e.g. solubility etc.).
ii. Cleaning agents (solvents).
iii. Compatibility of cleaning agents with the material from which the equipment is made.
iv. Volumes of used cleaning and rinsing agents (water, solvents etc.).
- Rinsing time (under running water where possible).
- Quality of utilities (water for washing and rinsing, air for drying, etc.).
- Cleaning sections and the sequences of operations.
- Time of draining and drying of equipment.
- Duration and frequency of cleaning.
- Interval between cleaning and the use of the equipment.
- Status of the equipment (clean, unclean etc.).
- Trained and responsible personnel for implementation of cleaning procedures.
- Cleaning instructions should be approved by responsible persons from Production and Quality Assurance.
- 4.6 Types of Cleaning
- A. Type “A” Cleaning Procedure
- This procedure is applicable in case of changeover from one batch to next batch of the same product & lower potency to higher potency of similar product if provided color is same.
- During changeover of batches between same products and at the end of every shift.
- During changeover of ascending strength of same product provide same colour and flavor.
- Before the usage of equipment lying unused for more than 72 hours which may be extended upto 96 hours.
Following steps will be followed for the cleaning procedure:
- For Type A cleaning Isolate the equipment from the electric mains.
- Remove the left over material from equipment and the surrounding area.
- Clean the equipment from inside and outside with clean lint free dry cotton cloth.
- Clean the surrounding area using vacuum cleaner or any other suitable mode.
- Use Vacuum cleaner to remove loose dust from all the surfaces including areas, which are difficult to access by hand.
- Clean some equipment/part of the equipment like Dryer trolley, sieves etc. in which it is not possible to remove the powder physically will be clean by following the Type “B” procedure.
- B. Type “B” Cleaning Procedure
This procedure is applicable in the following conditions:
- During changeover of batches between higher strength to lower strength of same products and next molecule is different from previous one or if the formulation is same except colour/ flavor of same formulation.
- In case of campaign batches that is same strength of same products after completion of five batches.
- If the equipment is unused for five days then Type B cleaning shall be performed before usage of same equipment.
- In case of any major maintenance work/ preventive maintenance work carried out which may affect the product quality during production.
- When next product & batch is not known.
Following steps will be followed for the cleaning procedure:
- For Type –B cleaning Switch “OFF” the supply to the equipment from main line.
- Isolate the equipment from the electric mains.
- Put potable water in the equipment & Scrub with nylon scrubber till all the adhering material is removed.
- Wash the equipment from inside and outside with potable water to remove adhering material to the surface of the equipment.
- Finally rinse the equipment with purified water.
- These procedure to be followed to clean the whole equipment, area, tables, trolleys, raiser grills, pendants or any other item which can contribute to cross contamination.
- For the areas which are difficult to clean in any equipment or areas needs to be cleaned with water-jet using water jet machine.
- Send intimation to QC for analysis of rinse water.
- Clean the equipment with lint free dry cotton cloth and allow it to air dry.
- Lint producing materials such as rags, towels must not be used to dry the equipment. Use only non fiber shedding cloth.
4.7 Method of Sampling
Sampling methods which will be used during validation of cleaning of production equipment must be selected in advance and stated in the protocol of qualification of processes, as well as the surface and/or volume of the taken sample.
It is best to combine swabs and rinses for chemical and microbiological testing, swab and rinses is taken from places as per SOP.
4.8 Method of Analysis
a. Methods of analysis used for determination of possible contaminant residues must be specific and sensitive.
b. Parameters to be taken into consideration in selection of the method of analysis as per analytical method validation protocol.
c. The methods of analysis used during cleaning validation must also be validated and stated in the process qualification protocol.
d. The method of analysis and sampling method must be combined to enable as efficient as possible removal of contaminant from the surface of the equipment and the level of recovery with which this is achieved should be determined. This should be done before making any conclusions based on results of analysis of samples, since negative result may also arise due to poorly selected sampling technique.
4.9 Calculation of Acceptance Criteria
Acceptance criteria for cleaning method verification will be defined for each product with the consideration of regulatory requirement.
Any one or combination two or more of the following will follows:
a. No more than 0.001 part of smallest therapeutically dose of any product will appear in the maximum daily dosage of another product.
i. Consider the 0.001 dose criterion for product A. If the next product on the production schedule is product B (low strength), equation 1 is used to calculate the limit for product A as follows: Milligrams of active ingredient in product A permitted per 25 cm2 swab area is equal to
I/J x K/L x M
I = 0.001 of the smallest strength of product A manufactured/day expressed as mg/day and based on the number of milligrams of active ingredient.
J = Maximum number of dosage units of product B taken/day.
K = Number of dosage units per batch of final mixture of product B.
L = Equipment surface area in common between products A and B expressed as square cm.
M = 25cm²/swab.
b. No more than 10 PPM of any product will appear in another product.
Below mentioned Equation is used to calculate the limit for product A if the next product on the production schedule is product B (low strength) as follows: Milligrams of active ingredient in product A permitted/25 cm2 swab
R x S/T x U
S = Number of kilograms per batch of final mixture of product B.
T = Equipment surface area in common between products A and B expressed as square inches.
U = 25 cm.2/swab
- Maximum Allowable Carryover (MAC) Method Maximum Allowable Carryover (MAC) can be determined by the following formula:
TD x BS x SF
MAC = ——————-
TD = Single therapeutic dose
BS = Batch Size of the next product to be manufactured on the same equipment
SF = The safety factor i.e. 1/1000
LDD = The largest daily dose of the next product to be manufactured in the same equipment.
CSA = Common Surface Area in cm²
a. The basic documentation on cleaning validation includes Cleaning Validation Protocol.
b. Cleaning Validation Protocol is a documented plan, based on the principal validation plan.
4.11 Change Control
- All aspects of cleaning should be included in the change control system in order to obtain an overview of the proposed or implemented changes, which includes determining whether a corrective action will have impact on the rest of the system and validation status.
- Cleaning procedures, methods of analysis, equipment, cleaning agents, and product formulations must be documented before the validation. Changes of procedures or documents must be documented and approved by the responsible and authorized person.
- When the change is of such a nature as to significantly change the philosophy of the validation of cleaning, re-validation should be performed. Re- validation is the repeating of the initial validation with the objective to ensure that the changes will not have impact on the quality of products and production.
4.12 Cleaning Validation Protocol
Cleaning validation exercise shall be carried out as per the validation protocol specific for a product
a. A unique number shall be given to each Cleaning Validation Protocol.
b. Protocol shall be 09 characters long and it shall be numbered as follows:
Where, “QA” denotes Quality Assurance
“/” marking for gap between two numerical or words.
“CV”denotes the Cleaning Validation Protocol.
“/” [Slash] marking for gap between two numerical or words.
“001” denotes the serial no. of protocol i.
“/” [Slash] marking for gap between two numerical or words.
“00”denotes the version No. of protocol e.g. 01, 02, 03……..
c. The cleaning validation protocol shall be prepared by Quality Assurance officer or above as per instructions available for the product under study. The protocol formats shall be prepared.
d. Only validated or Pharmacopoeial methods will be used for the Cleaning Validation Study.
e. The analytical methods used to detect residuals or contaminants will be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company.
Revalidation of cleaning procedure will be done any of the following condition.
a. Failure of Routine Monitoring.
b. Change in Cleaning Procedure.
c. Change in Product, process or equipment.
d. Change in solvent used for cleaning.
e. New Product having least solubility.
Trainer : Head – Quality Assurance
Trainees : Staff of all the departments
Master Copy : Quality Assurance
Controlled Copy : Quality Assurance , Quality control
|Annexure No.||Title||Format No.|
- 7. REFERENCES
|SOP||Standard Operating Procedure|
10.0 REVISION HISTORY OF CHANGE
|Sr. No.||Date||Revision Details||Revision No.|