SOP Title: Rinse And Swab Sample Analysis
- Objective:
To lay down the procedure for Rinse and swab Sample Collection of Equipments or Machines and Analysis.
- Scope:
This SOP is applicable for Rinse and Swab Sample Collection of Equipments or Machines and Analysis of previous product residue on Equipments or Machines used for manufacturing purpose.
- Responsibility:
- Quality Control Department: To prepare and review the SOP. To follow the procedures laid down for Rinse and Swab Sample Collection of Equipments or Machines and Analysis in Quality Control Department as per this SOP.
- Quality Assurance Department: To review and approve the SOP and Annexures.
- Accountability:
Head Quality Control Department, Head Quality Assurance Department
- Procedure:
| 5.1 | Residual Sample Collection : | |||||||||||||||||||||||||||||||||||||
| 5.1.1 | Quality Control chemist should prepare the necessary solvent and accessories for swab or rinse collection. | |||||||||||||||||||||||||||||||||||||
| 5.1.2 | After receiving the intimation of swab or rinse sample analysis from concerned department, analyst/supervisor shall make entry in “Residual Sample Entry Register” as per Annexure. | |||||||||||||||||||||||||||||||||||||
| 5.1.3 | Quality Assurance personnel shall go to the concerned Department for collection of sample. | |||||||||||||||||||||||||||||||||||||
| 5.1.4 | If Quality Assurance personnel visually observed any visual residue or lack of cleaning during swab sampling or rinse water collection, he / she should not collect the sample up to satisfactory washing done as per SOP of washing for particular equipment or machine. | |||||||||||||||||||||||||||||||||||||
| 5.1.5 | Purified water shall be used for washing and rinsing, if previously drug is water soluble and physical structure of Equipment/Machine is easily washable. After washing collect the rinse sample. | |||||||||||||||||||||||||||||||||||||
| 5.1.6 | Take swab sample from difficult to clean area of Equipment/Machine and water insoluble drugs to check previous product residue after cleaning. | |||||||||||||||||||||||||||||||||||||
| 5.1.7 | Use Ethanol as a solvent for water insoluble drug swab sample collection or any other solvent can be used as per STP. | |||||||||||||||||||||||||||||||||||||
| 5.1.8 | Sampling Methods for Surface Residue
1.Rinsing 2.Direct Surface Sampling (Swab sampling) |
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| 5.2 | Rinse Sampling: | |||||||||||||||||||||||||||||||||||||
| 5.2.1 | An indirect sampling method is rinse sampling. A small sample of the solution collected from the last rinse cycle of the cleaning process is analysed for the compound of interest and the residual limit is back-calculated according to the volume of solution and the contact area. There are generally two assumptions inherent in this method. The first is that the target residue is efficiently extracted into the rinsing solution. The second is that all parts of the contaminated surfaces are cleaned equally. One fairly significant advantage is the ease of collecting a part of the final rinse solution drained from the equipment. Another is that it allows evaluation of residues from all parts of the surface irrespective of the difficulty of reaching them with a swab. This makes rinse sampling ideal for clean-in-place (CIP) systems sealed systems or large-scale equipment that is difficult to disassemble. During cleaning validation program, rinse sample can be directly analysed by above methods and there is no need to develop specific preparation for rinse sample.
Depending upon the concentration and number of washing, final rinse sample can be analysed and based on results residue can be calculated. |
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| 5.2.2 | Production person shall wash the instrument as per defined in respective SOP | |||||||||||||||||||||||||||||||||||||
| 5.2.3 | After Receiving Rinse sample/ Swab sample, Assign Analytical Reference Number (A. R. No.) as “RS/YY/NNN”
Where, ‘RS’ stands for ‘Residual Sample’ ‘YY’ stands for ‘Last two digits of the current year’. ‘NNN’ stands for ‘Serial number i.e. 001, 002 and so on’. |
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| Rinse Sample Analysis: | ||||||||||||||||||||||||||||||||||||||
| 5.2.4 | Proceed for analysis as per STP/GTP for Rinse/Swab analysis of respective drug. | |||||||||||||||||||||||||||||||||||||
| 5.2.5 | Enter all the details in Residual Sample Data Sheet. | |||||||||||||||||||||||||||||||||||||
| 5.2.6 | Test Preparation: – Take direct reading of rinse sample given from manufacturing for Analysis. If required dilute it with diluent. | |||||||||||||||||||||||||||||||||||||
| 5.2.7 | Blank Preparation: – Use cleaning solvent / diluent as Blank solution. (Refer STP/GTP) | |||||||||||||||||||||||||||||||||||||
| 5.2.8 | Standard Preparation (10ppm): – Prepare 10ppm concentration standard solution by weighing accurately and diluting with suitable diluent. (Refer STP/GTP) | |||||||||||||||||||||||||||||||||||||
| 5.3 | Swab sampling: | |||||||||||||||||||||||||||||||||||||
| 5.3.1 | Direct surface sampling can be carried out in a number of ways, but the most common and widely accepted is swabbing. This involves wiping a predetermined area of the equipment with a swab that has been moistened with a solvent determined by the contaminating compound. Usually the surface is wiped with one side of the swab using a certain number of strokes, then the swap is flipped and the surface is wiped at 90° to the first series of stokes as shown in the following figures in refer point no. 5.3.5.
Swab technique The recommended strategy is to thoroughly wet the swab head in the solvent and then squeeze the excess solvent from the swab head using the side of the solvent container. It is important to ensure that both sides of the swab are squeezed out. |
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| 5.3.2 | Amongst the advantages of the swabbing method is the fact that insoluble or slightly soluble residues on the surface are more readily removed by physical “rubbing” than is the case in (for example) rinsing. It also permits direct sampling from accessible,
· Insoluble n dried residues may be removed by physical action · When accessible hardest to clean area can be sampled, indicating a likely maximum level of the residue Swab selection is important in swabbing method. Swab sampling is technique dependant |
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| 5.3.3 | Mark a 2 x 2 inch or 5 x 5 cm area on critical surface of the Equipment or Machine for Swab Sample Collection. | |||||||||||||||||||||||||||||||||||||
| 5.3.4 | Quality Assurance personnel should collect the swab with cotton bud or swab stick previously moisten with suitable solvent as per below figure: | |||||||||||||||||||||||||||||||||||||
| 5.3.5 | Swab Sampling: this is a method for sampling from the surface by a small stick having cotton wrapped on one or both end. Following steps shall be taken for swab sampling:
1. Pick the swab and dampen it with diluents. 2. Put the swab template on the specified surface of the equipment. 3. Swabbing shall be done using about 10 strokes as shown in below diagram.
Sideways Downward Diagonal Diagonal Left to Right Right to Left
Snap swab head at the notch along edge of swab stick and allow the swab head to fall into Test Tube/vial. |
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| Swab Sample Analysis: | ||||||||||||||||||||||||||||||||||||||
| 5.3.6 | Test Preparation: – Take 1 Swab (given from manufacturing for Analysis) in a test tube, add 10ml of diluent and sonicate for 5minutes. | |||||||||||||||||||||||||||||||||||||
| 5.3.7 | Blank Preparation: – Take 1 Swab (intact/pure swab stick) in a test tube, add 10ml of diluent and sonicate for 5minutes. | |||||||||||||||||||||||||||||||||||||
| 5.3.8 | Standard Preparation (10ppm): – Prepare 10ppm concentration standard solution by weighing accurately and diluting with suitable diluent. (Refer STP/GTP) | |||||||||||||||||||||||||||||||||||||
| 5.3.9 | Proceed for analysis as per STP/GTP for Rinse/Swab analysis of respective drug. | |||||||||||||||||||||||||||||||||||||
| 5.3.10 | Enter all the details in Swab Sample Data Sheet. | |||||||||||||||||||||||||||||||||||||
| 5.3.11 | If result observed out of limit analyst should intimate to Quality Assurance Department for investigation or re-cleaning of the Equipment/Machine. | |||||||||||||||||||||||||||||||||||||
| 5.3.12 | If result observed under limit analyst should prepare a release report of swab analysis or rinse analysis with remark and data should be filed in proper manner. | |||||||||||||||||||||||||||||||||||||
| 5.3.13 | After the analysis, analyst should hand over the Rinse/Swab Sample Data Sheet to Supervisor/Reviewer analyst for data checking. | |||||||||||||||||||||||||||||||||||||
| 5.3.14 | Quality Control Head shall verify and approve the Residual Sample Data Sheet. | |||||||||||||||||||||||||||||||||||||
| 5.3.15 | Production or concerned Department can receive the photocopy of Residual Sample Data Sheet for their reference (If required). | |||||||||||||||||||||||||||||||||||||
| 5.3.16 | Methods Used for Analysis of Rinse/Swab :-
1) Specific Test Methods 2) Non-Specific Test Methods Refer below Table; |
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| 5.4 | Acceptance criteria | |||||||||||||||||||||||||||||||||||||
| 5.4.1 | a. NMT 10 ppm of any product will appear in another/ next product.
b. NMT 0.1 % of the normal therapeutic dose of any product will appear in maximum daily dose of the sub sequent product. c. For certain allergic ingredient, penicillin cephalosporin of steroid and cytotoxic, the limit should be below the limit of detection. |
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| 5.4.2 | The limit for the microbiological bioburden criteria for product contact surface should NMT 100 cfu / swab. | |||||||||||||||||||||||||||||||||||||
| 5.5 | Calculation | |||||||||||||||||||||||||||||||||||||
| 5.5.1 | 10-ppm criteria: Maximum 10 ppm level residual contamination of the previous active pharmaceutical ingredient in the product is widely accepted in the pharmaceutical industry.
Hypothetical worst case product identification of Maximum Allowable Carryover (MAC/swab) as per 10-ppm criteria in Nestor Pharmaceuticals Limited is derived as per following formula:
Where, R : 10 mg active ingredient of product A in one kg of product B S : Smallest batch size (For e.g. 5.0 kg batch size is selected hypothetically for worst MAC calculation). T : Total Surface area of equipment’s F : Recovery factory (Recommended 0.75). U = Swab area i.e. 4X4 sq. inch For e.g. 10 X 5.0 X 4 X 4 X 0.75 53000 = 0.0113mg/swab = 0.0113 mg/swab X 1000 = 11.3 mcg/swab
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| Calculation for MAC (maximum allowable carryover ):- Therapeutic dose based criteria:- | ||||||||||||||||||||||||||||||||||||||
| 5.5.2 | 1/1000th of smallest recommended daily dose Criteria:
Maximum Allowable Carryover (MAC) of previous product in the subsequent product is calculated as:
Where, SRDD = Smallest Recommended Daily Dose of product among the all products in mg. SBS = Smallest Batch Size in kg. SF= 1/1000, safety factor U = Swab area i.e. 4X4 sq. inch LRDD = Largest Recommended Daily Dose of product among the all products in mg. TSAR = Total Surface area of equipment’s in sq. inch F: Recovery factory (Recommended 0.75). |
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| 5.5.3 | Swab recovery test shall be a part of the method validation to estimate the recovery during swabbing. | |||||||||||||||||||||||||||||||||||||
| 5.5.4 | The recovery shall be accounted for calculation of the cumulative retention of residue. | |||||||||||||||||||||||||||||||||||||
| 5.5.5 | Safety Factor Term:-
Options to apply safety factors uniformly within a plant – For Topical product: 10 to 100* – For Oral Dosage Product: 100 to 1000* – For Parental/ Ophthalmic product: 1000 to 10000 – For Research investigational product: 10000 to 100000 – *Note Significant rationale must be given if safety factor is less than the industry-standard 1000 |
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| Clean Hold Time (CHT) and Dirty Hold time (DHT):- | ||||||||||||||||||||||||||||||||||||||
| 5.5.6 | Clean hold Time:
– Following Cleaning, how long equipment remains ‘clean’ before reuse. – Not concerned with the process residue: focus is on controlled storage( bioburden proliferation ) Dirty Hold time: – How long ‘dirty’ equipment can remain dirty prior to cleaning. – Generally, longer DHT → increasingly difficult to clean |
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- Definitions / Abbreviations :
- Definitions :
- Cleaning: Removal of Residue and Contaminants to be a Controlled level. The residue and contaminates Can be by cross contamination from previously manufactured products equipment or from the procedure( detergent/sanitizers) or degradation product resulting from the cleaning process itself, as well as microorganism*.
- Cleaning verification: A quality control process for determining the effectiveness of a cleaning process for a specific cleaning event or to release of equipment for use.
- Cleaning Validation: A methodology used to assure effectiveness and consistency of cleaning process to remove residue and contaminates.
- Type A Cleaning: It is dry cleaning process performed between the same type of products or campaign batches generally called as batch to batch changeover. This type of cleaning consists of removal of drug powders from the surface with the help of clean cloth or scraper/scrubber.
- Type B Cleaning: It is wet cleaning process in which cleaning solution is used for cleaning. This is performed in following cases:
- MACO: Maximum allowable carryover is the upper limit of residue that can be allowed after cleaning process. Cleaning procedure should be efficient to remove the residue below the MACO value.
- Rinse Sampling: this is the method by which all the contact surface of the cleaned equipment is rinsed with specified amount of water then collecting certain volume of the rinse water into a vial.
- Cleaning Hold Time: Cleaning hold timeis considered to be the time between the completion of cleaning and the initiation of the subsequent manufacturing operation. Dirty hold time is the time between the end of manufacturing and the beginning of the cleaning process.
- Abbreviations :
| Abbreviation | Expansion |
| SOP | Standard Operating Procedure |
| QC | Quality Control |
| STP | Standard Testing Procedure |
| GTP | General Testing Procedure |
| QA | Quality Assurance |
| UV | Ultra Violet |
| No. | Number |
| NMT | Not more than |
| cm | centimeter |
| ppm | parts per million |
*Note – Ready to use SOP available in “DOWNLOAD” Section.