In this article, we will discuss process validation in the pharmaceutical industry(Alvamax Drench).
Objective:
To conduct the process validation of the manufacturing process for the Alvamax 100 Drench manufactured at the Vetlab(Pvt) Ltd(liquid section). The Validation study shall be conducted for the generation of sufficient data to establish documentary evidence and to provide assurance that the product can be manufactured on a commercial scale, meeting all its quality attributes in a consistent manner.
Three consecutive commercial batches (having the same batch size) of Alvamax 100 Drench shall be taken for process validation.
- Scope:
This protocol shall be applicable for the first three consecutive commercial-scale batches manufactured with specific batch size & equipment and operating parameters for the Alvamax 100 Drench at Vetlab(Pvt) ltd
4.0 Validation Approach:
The validation approach shall be prospective and the following things shall be reviewed:
4.1 Review the qualification documents of equipment and related utility systems that shall be employed for the manufacturing of batch.
4.2 Review the calibration record of instruments used in validation.
4.3 Review the master formula records.
4.4 Review the specification and analytical procedures of raw materials and packing materials.
4.5 Review the specification and analytical procedures for in-process & finished products.
5.0 Reason for Validation: New product in the manufacturing facility.
6.0 Revalidation:
Revalidation shall be done in the following cases
6.1 Any major change in the manufacturing process may affect the quality of the product.
6.2 Any change in the batch size.
6.3 Any change in the batch formula.
6.4 Change in the manufacturing site.
6.5 Any modification in any critical equipment.
6.6 Any major modification in the related utility system.
6.7 Any change in the specification and/or change in the source of active pharmaceutical ingredient (API).
6.8 Any change in primary packaging material.
7.0 Responsibilities:
7.1 Quality Assurance shall be responsible for:
7.1.1 Preparation, approval, and training of validation protocol, review of the data compiled, review of deviations (if any), monitoring the process as per the process parameters, and for withdrawal of validation samples.
7.1.2 Review of facility, equipment qualification, and utility validation reports.
7.1.3 cGMP compliance during the manufacturing process, review, and evaluation of the data/results generated during validation.
7.1.4 Preparation of process validation summary report, review, and its approval.
7.2 Production shall be responsible for:
7.2.1 To execute the batches as per the batch production record and process validation protocol.
7.2.2 Compilation of data related to the manufacturing area and furnishing the same for review.
7.2.3 Review of protocol and summary report.
7.3 Quality Control shall be responsible for:
7.3.1 Raw material and packing material analysis
7.3.2 In-process and finished product samples analysis as per the sampling plan.
7.3.3 Collection and review of in-process and finished product analysis data.
7.3.4 Submission of data /results to QA for review and evaluation.
8.0 Reference Documents:
8.1 BMR No:
8.3 Specification No.:
9.0 Procedure:
9.1 Product Details:
| PRODUCT NAME | : | Alvamax 100 drench |
| GENERIC NAME | : | Albendazole
|
| SHELF LIFE | : | 2 Year |
| STORAGE CONDETION | : | Store in a cool and dry place |
| LABEL CLAIM | : | Each ml contain :
Albendazole 100mg |
| BATCH SIZE | : | 500 liter |
| MARKET | : | Yes |
9.2 Raw Material Details:
Following raw materials were used in the formulation of Alvamax 100 Drench. All the raw materials were tested in the quality control department of Vetlab Private Limited.
Individual certificate of analysis was generated and it was assured that all the materials are complying with raw material SOP of the industry.
| Item No. | Ingredient | Quantity
|
Units |
|
|
Albendazole | 50.0 | Kg |
|
|
Xanthan Gum | 1.5 | Kg |
|
|
CMC Sodium | 0.50 | Kg |
|
|
Silicon Emulsion | 2.0 | Kg |
|
|
Glycerin | 25.0 | Kg |
|
|
Methyl Paraben Sodium | 0.50 | Kg |
|
|
Purified Water qs. to | 500.0 | Liter |
- Packing Material Details:
| Item No. | Packaging material | Pack size |
Quantity |
| 1 | Plastic Cane 1 Liter | 1000ml | 550 |
| 2 | Plastic cap | 1000ml | 550 |
| 3 | Induction seals | 35mm | 550 |
| 4 | Stickers (FRONT) Alvamax Drench | 1000ml | 550 |
| 5 | Stickers (BACK ) Alvamax Drench | 1000ml | 550 |
| 6 | U/BOX 1 LITRE Alvamax Drench | 1000ml | 550 |
| 7 | Shipper #10 | 1x 12 | 50 |
- Equipment Details:
| Sr.# | Code | Machinery
/equipment Name |
Capacity | Qualification/
Calibration |
Opr training | Observation | REMARKS /SIGN
|
||
| B.#
0 |
B.#
0 |
B.#
0 |
|||||||
| 1 | S.S. Manufacturing Vessel | 500 Litre | Ok | Yes | Ok | Ok | Ok | Ok | |
| 2 | S.S. Transfer Pump | 500 Litre | Ok | Yes | Ok | Ok | Ok | Ok | |
| 3 | Automatic filling machine | 300cane /hour | Ok | Yes | Ok | Ok | Ok | Ok | |
| 4 | Induction Sealing Machine | NA | Ok | Yes | Ok | Ok | Ok | Ok | |
| 5 | Bottle Blowing Machine | NA | Ok | Yes | Ok | Ok | Ok | Ok | |
- Quality Control Instruments:
| Sr.# | Code | Instrument Name | Qualification/
Calibration |
Analyst training | Observation | REMARKS /SIGN
|
||
| B.# | B.# | B.# | ||||||
| 1 | CONDUCTIVITY METER( EC 215) | Ok | Yes | Ok | Ok | Ok | Ok | |
| 2 | PH METER (HI 2210 HANNA) | Ok | Yes | Ok | Ok | Ok | Ok | |
| 3 | UV-VIS SPECTROPHOTOMETER ( T -80 PG) | Ok | Yes | Ok | Ok | Ok | Ok | |
| 4 | ANALYTICAL BALANCE ( SHIMADZU ATX 224) | Ok | Yes | Ok | Ok | Ok | Ok | |
| 5 | HPLC WATERS 486 DETECTOR,515 PUMP | Ok | Yes | Ok | Ok | Ok | Ok | |
| 6 | MEMERT OVEN | Ok | Yes | Ok | Ok | Ok | Ok | |
| 7 | MEMMERT INCUBATOR(HOT) | Ok | Yes | Ok | Ok | Ok | Ok | |
| 8 | INCUBATOR COLD | Ok | Yes | Ok | Ok | Ok | Ok | |
| 9 | AUTOCLAV | Ok | Yes | Ok | Ok | Ok | Ok | |
| 10 | LAMINAR AIR FLOW | Ok | Yes | Ok | Ok | Ok | Ok | |
| 11 | MICROPIPETTE | Ok | Yes | Ok | Ok | Ok | Ok | |
- Manufacturing Process:
| Steps | MANUFACTURING METHOD | Checked by | Observation | REMARKS /SIGN
|
|||
| Prod-Pharmacist | QAI | B.# | B.# | B.# | |||
| 1 | Take about 250 liters of purified water in a 500 liter st. st. processing vessel fitted with silverson mixer and add the following ingredients one by one, while mixing after each addition and mix well to have a clear solution; methyl paraben sodium and Propyl paraben sodium | Complies | Complies | Complies | Ok | ||
| 2 | Add following ingredients to the processing vessel one by one, while mixing after each addition; xanthan gum and CMC sodium. Continue mixing for about 20 minutes after the last addition and add glycerin. Mix for about 10 minutes and keep the above liquid a side for at least 2 hours | Complies | Complies | Complies | Ok | ||
| 3 | Mix liquid for about 10 minutes and then add one by one Albendazole and silicone emulsion, direct into the processing vessel, while continue mixing with the help of silverson mixer. | Complies | Complies | Complies | Ok | ||
| 4 | Take About 30 liters of purified water in a separate 200 liters processing vessel and add the following ingredient citric acid,.Add this clear solution to the main processing vessel and continue mixing.
Final add the purified water to make up the volume and mix it for 15 minutes
|
Complies | Complies | Complies | Ok | ||
| 5 | Request Quality Control Department to draw the sample for analysis and after getting release for filling from Quality Control Department fill the drench in the filling area into 1000ml,100ml white plastic canes. | Complies | Complies | Complies | Ok | ||
- Sampling Plan:
Finally 500 ml of Alvamax 100 Drench sample was taken, then tested for critical in process parameters mentioned in process validation protocol. Sampling location for each batch is from Top, Middle and Bottom of the manufacturing vessel.
- In-process Checks & Critical Control Points:
- A) Description Of In Process Parameter Of Alvamax 100 Drench
| TEST PARAMETERS
|
SPECIFICATIONS
|
Observation
|
REMARKS /SIGN
|
||||
| B.#
|
B.#
|
B.#
|
|||||
| Appearance
|
Light blue colored suspension | Complies | Complies | Complies | Ok | ||
| pH
|
4.5 to 5.5 at 25° C | 4.98 | 4.92 | 5.09 | Ok | ||
| Viscosity | 120 – 250 CPS. at 25°C
Spindle # 2, 100 rpm,T,30-50% |
124.3 cps | 129 cps | 132.2 cps | Ok | ||
| Assay | Albendazole
|
90-110% |
Top
|
99.03% | 100.13% | 98.54% | Ok |
| Middle
|
98.98% | 101.89% | 99.67% | Ok | |||
| Bottom | 100.25% | 100.50% | 99.74% | Ok | |||
- b) Details of Filling and Sealing Observation
| S. #
|
Test
|
Acceptance criteria
|
Observation
|
REMARKS /SIGN
|
||
| B.#
|
B.#
|
B.#
|
||||
| 1 | Bottle /can blowing
|
Compressed air pressure
NLT 5.0Kg/cm² Compressed air blowing time 1.8sec per can/bottle |
Complies | Complies | Complies | Ok |
| 2 | Particulate matter
|
Visible particulate matter: canes should be free from visible particulate matter. | Complies | Complies | Complies | Ok |
| 3 | Volume variation
|
Individual volume ±3% of target fill volume average fill volume: ±2% of target fill volume. | Complies | Complies | Complies | Ok |
| 4 | closure integrity test cap sealing | No Defective cane,
No sealing defects, |
Complies | Complies | Complies | Ok |
- C) Environmental Condition of Manufacturing & Filling Area Area.
| S. #
|
Parameters
|
Area
|
Acceptance criteria
|
Observation
|
REMARKS /SIGN
|
||
| B.# | B.# | B.# | |||||
| 1 | Temperature (◦c)
|
Liquid mfg area
Liquid filling area |
NMT 25ºC
NMT 25ºC |
21ºC
21ºC |
22ºC
22ºC |
22ºC
23ºC |
Ok |
| 2 | Relative Humidity
(%)
|
Liquid mfg area
Liquid filling area |
30-60%
30-60% |
53%
55% |
51%
51% |
53%
52% |
Ok |
| 3 | Differential
Pressure
|
b/w corridor & liq mfg area
b/w corridor & liq filling area
|
+ve Pressure between 10-15 pascal
+ve Pressure between 10-15 pascal |
Complies | Complies | Complies | Ok |
| 4 | Manufacturing area
Particle Count
|
Viable particle count
Non viable particle count |
NMT 100 col
NA |
Complies | Complies | Complies | Ok |
| 5 | Filling Area
Particle Count
|
Viable particle count
Non viable particle count |
NMT 100 col
NA |
Complies | Complies | Complies | Ok |
- Finished Product Specification:
| S. #
|
Test | Specification | Observation |
REMARKS /SIGN
|
||
| B.#
|
B.#
|
B.#
|
||||
| 1 | Description
|
Light blue colored suspension | Complies | Complies | Complies | Ok |
| 2 | Identification by
|
HPLC | Complies | Complies | Complies | Ok |
| 3 | pH | 4.5 to 5.5 at 25° C | 5.0 | 4.95 | 5.07 | Ok |
| 4 | Viscosity | 120 – 250 CPS at 25°C
Spindle # 2, 100 rpm,T,30-50% |
125.2 cps | 129.0 cps | 132.2 cps | Ok |
| 5 | Assay | Albendazole
90-110% |
99.55% | 100.17% | 99.70% | Ok |
| 6 | Bacteria | NMT 100 CFU/ml | 05cfu/ml | 17cfu/ml | 6cfu/ml | Ok |
| 7 | Yeast /Mould | NMT 10 CFU/ml | 3cfu/ml | 04cfu/ml | 02cfu/ml | Ok |
| 8 | Pathogens
Escherichia coli,Salmonella aureus Pseudomonas aeruginosa,Staphylococcus aureus |
shall be absent /ml | Absent | Absent | Absent | Ok |
10.0 Stability: If acceptance criteria at all the stages of 3 batches are satisfied, the process to be accepted as validated for manufacturing the product at the site, Vetlab(Pvt)Limited. The Validation batches shall be introduced for complete stability studies as per stability protocol.
11.0 Deviations: Any deviation from the protocol related to the manufacturing process, raw materials, equipment used, sampling, in-process controls and analytical methods should be authorized and documented in the batch manufacturing record as well as the validation report.
12.0 Conclusion: Based on the results of all the 3 batches, suitable conclusions will be drawn with respect to the suitability of the proposed method of manufacture for the Alvamax 100 Drench. Conclusion about the suitability of the validation batches for stability testing would be drawn.
13.0 Documentation and Reporting: Validation protocol, batch manufacturing records, batch packing records, analytical reports, stability protocol, stability data and stability report of all the three validation batches have to be compiled, reviewed and to be documented. A process validation report shall be prepared.
14.0 Report Approval: Process validation data shall be compiled and report shall be prepared by Officer– QA. The report shall be checked by QC Manager-Production Manager and shall be approved by QA Manager.
Sign:
Date:
Q.A officer
Sign:
Date:
Quality Control Manager
Sign:
Date:
Quality Assurance Manager
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