PROCESS VALIDATION PROTOCOL OF TACROLIMUS CAPSULES

PROCESS VALIDATION PROTOCOL 

TACROLIMUS CAPSULES

Tacrolimus is administered in conjunction with other medications to inhibit the rejection of a kidney, heart, liver, or lung transplant. This particular medication falls under the category of immunosuppressants, which function by diminishing the efficacy of your body’s immune system. Consequently, this aids in the acceptance of the newly transplanted organ as if it were an inherent part of your own body.

The mechanism of action

Tacrolimus involves its role as an immunosuppressant. In individuals who have undergone organ transplantation, it functions by suppressing the immune response of the body, thereby facilitating the acceptance of the transplanted organ as part of the individual’s own body. In the case of allergic eye disease, Tacrolimus operates by reducing the production of certain chemicals, including histamine, which are responsible for causing symptoms such as inflammation, redness, and swelling in the eyes.

Adverse reactions commonly associated with Tacrolimus include elevated blood glucose levels, sleep disturbances, heightened potassium levels in the blood, hypertension, kidney toxicity, neurotoxicity, gastrointestinal disorders, diabetes, susceptibility to infections, reduced appetite, electrolyte imbalances, fluid retention, and abnormalities in blood cell counts.

Label claim:

Each hard gelatin capsule contains:

Tacrolimus …………. ……… 1.0 mg

Approved Colours Used in Capsule Shells

Batch Size: 120,000 capsules                 

Shelf Life: 24 months  

PROTOCOL CONTENTS

Section Title
Protocol Contents
Protocol Approval Sheet
Objective
Scope
Responsibility
Validation Team Members
Abbreviations
Pre-requisite for Validation
Manufacturing Procedure Under Validation
Critical Process Steps and Process Parameters for Validation with Justification
Process steps – Sampling and Analysis Plan with Acceptance Criteria
Hold Time Studies
Revalidation
OOSs and Investigations
Validation Report
Reference Documents                                         
List of Annexures / Formats Attached

PROTOCOL APPROVAL 

This is a specific protocol for the Process Validation of TacrolimusCapsules  1.0 mg  Capsules which is manufactured at a solid oral manufacturing facility.

 Objective

To provide documented evidence with a high degree of assurance that the manufacturing process is capable of producing the finished product consistently of the required quality, meeting its predetermined specifications and quality attributes.

Scope

This concurrent process validation protocol is applicable to carry out the process validation for PanGraf 1.0 (TacrolimusCapsules 1.0 mg Capsules) on three consecutive batches.

Responsibility

Quality Assurance: Preparation, review, and approval of process validation protocol.

R&D: R&D to approve the process validation protocol

Production: Production to approve the process validation protocol.

Quality Control: QC to approve the process validation protocol.

Process Development: To review the process validation protocol.

IPQA:  Sampling of samples as per the sampling plans discussed in
this process validation protocol.

Engineering: To provide support concerning utilities and equipment

Regulatory Affairs: Review And Approval Of Process Validation Protocol.

Validation Team Members

The validation team is comprised of Trained  representatives from the following departments:

• Production
• R&D
• Quality Control
• In-process Quality Assurance
• Quality Assurance
• Engineering

The validation team is authorized by the Head-QA or his/her designee.

Abbreviations

R&D: Research and Development

IPQA: In-process Quality Assurance

RSD: Relative Standard Deviation

NMT: Not More Than

NLT: Not Less Than

STP: Standard Test Procedure

LOD: Loss on Drying

GTP: General Test Procedure

Spec. No.        : Specification No.

RH%: Relative Humidity

IQ : Installation Qualification

OQ: Operational Qualification

PQ: Performance Qualification

IH: In-house

Representative Sample: A sample collection from one location/place; representing the characteristics of the whole batch/lot.

Composite Sample: A desired amount of sample shall be taken after the collection of samples from different locations in one sample bag.

Pre-requisites for Validation

Process Equipment

All equipment to be used for the manufacturing process is qualified as per IQ/OQ/PQ acceptance criteria. The following equipment is to be used for manufacturing of Tacrolimus Capsules  1.0 mg  Capsules.

• Vibro sifter 30”
• Conta Blender
• Comminuting Mill
• Automatic Filling Machine
• Tray dryer  and its area
• Coating pan conventional 42”
• Pressure Vessel
• Blister packing machine

Note: A list of equipment used in the manufacturing process is prepared and their operation and cleaning are done as per their Operation  & Cleaning  SOPs.

Equipment / Instruments used for In-process checks

The following calibrated equipment / Instruments are used for in-process checks.

Halogen Moisture Analyzer
Disintegration Test Apparatus
Analytical Weighing Balance
Vernier Caliper

The following specifications and Standard Test Procedures are referred for carrying out testing of validation samples.

• In-process
• Finished Product -Release

Testing of samples is   done as per the current version of the spec., STP’s and GTP’s 

Approved Raw Materials

The raw materials used for the manufacturing process are from approved vendors and all the Raw Materials are tested before the manufacturing process to ensure that materials are of acceptable quality before their use in the manufacturing.

Approved Raw Material List 

Ingredient
Solid Dispersion of Tacrolimus
Anhydrous Lactose
Magnesium Stearate
Empty hard gelatin capsule shell size “01”

Information related to raw materials shall be recorded

Manufacturing Procedure:

The manufacturing procedure in brief comprises of following steps:

Milling –

Mill, Anhydrous Lactose ( 10.48 kg) through Comminuting Mill fitted with 0.5 mm perforated screen at hammer forward orientation, sift through vibrosifter with sieve of mesh size 80. pass the material and collect the material in IPC.

Sifting –

Sift solid Dispersion of Tacrolimus 600.00 g through a Vibrosifter fitted with the sieve of mesh size 60 in an IPC container and mix in a Blenders bin. Mix the material using a conta blender at 6 RPM.

Blending –

Magnesium stearate was sifted through a vibro sifter fitted with the sieve of mesh size 60 and collected the material in a blender bin.

Blend the material using a conta blender for 03 minutes at 6 RPM.

Critical Process Steps and Process Parameters for Validation with Justification : 

Process Step	Process Parameters	Justification
DISPENSING	RH, Temperature	To record the environmental conditions during dispensing.
MILLING OF ANHYDROUS LACTOSE	Screen size, hammer orientation, sieve size, milling time, and integrity of sieve.	To record and evaluate the variability of critical process variables.
SIFTING OF SOLID DISPERSION OF TACROLIMUS	Sieve size, sifting time, and integrity of sieve.	To record and evaluate the variability of critical process variables.
LUBRICATION/ BLENDING	Blender rpm, Blending time and running capacity of blender, etc.	The dried granules are sized using Sifter Cum Multimill and further collected in a blender bin and blended with sifted and mixed post-granulation ingredients using Conta Blender. This process step is evaluated for adequate blending of the post-granulation ingredients by sampling the blended granules from 11 different locations from the blender bin after completion of blending. The assessment is taken through the determination of blend uniformity analysis (for Tacrolimus ) of samples collected from different locations. The blend is characterized through the determination of Bulk Density, Tapped Density, Angle of Repose, and Hausner Ratio on (200 gm) composite sample collected after completion of blending for 10 minutes at 6 rpm. Sampling is done by using a suitable sampling thief.
CAPSULE FILLING	The machine’s speed and reproducibility throughout the entire process.	This process step is evaluated by sampling the filled capsules at different intervals i.e. at the start, mid, and towards the end of the filling operation Samples are subjected to process checks for the determination of average fill weight, and uniformity of fill weight, average weight, lock length, disintegration time. QC sampling & testing are done against the established specifications at the start, middle & end to ensure the adequacy and correctness of the process. A composite sample is also withdrawn after filling and analyzed against the established specifications.It Can Influence the In Process Capsule Filling Characteristics
BLISTER PACKING	Blister Forming temperature, Sealing temperature & Machine speed	Temperature influences the blister forming, and sealing ability and thereby maintaining the integrity of the pack.

 

Process Steps – Sampling and Analysis Plan with Acceptance Criteria

Sampling is done as a Sampling plan. The process parameters are challenged in the three validation batches.

Process Step	Sampling and Analysis Plan  with Acceptance Criteria
Blending
Drying
Screening
Final mixing
Capsule filling

 

Hold Time Studies

Process Step

Hold Time Studies Sampling and Analysis Plan with Justification

BINDER SOLUTION                         CAPSULE FILLING

About 200 gm of blend is stored under controlled conditions of temperature & humidity. The binder solution samples are periodically withdrawn and the sample is subjected to analysis for Description, Loss on Drying, Assay, and microbial limit. Storage Environment Temperature: NMT 30ºC Relative Humidity: NMT 45% Test Method: Description, L.O.D  & Assays: Refer to Specification. Acceptance Criteria 0 day, 15th day, 30th day, 45th day, and 60th day Description: White to off–white, free-flowing powder. L.O.D:  Between 2.0 % w/w and 4.0 % w/w, determined at 105 ºC for 10 minutes. Assay: Each 187.5   mg of the complex contains not less than  90.0 %  and not more than 110.0 % (33.75 mg to 41.25 mg) of the label claim of  Tramadol  Hydrochloride Ph.Eur., C16H26 CI NO2 (37.5 mg). Microbial Limit: Refer to GTP No.: P-514-T for microbial limit testing as per USP Acceptance Criteria Microbial Limit: Total aerobic microbial count: NMT  500 cfu per g Total combined molds and yeast count: NMT 50cfu per g Escherichia coli: Should be absent Salmonella species: Should be absent Pseudomonas aeruginosa: Should be absent Staphylococcus aureus: Should be absent After completion of the capsule filling activity, about 1000 No. of filled capsules are stored under controlled conditions of temperature & humidity for carrying out hold Time Studies. The sampling shall be done on 0 day, 15th, 30th  & 45th day; the sample is tested for Description, identification, Average weight,  disintegration, Dissolution, Single highest impurity, total impurities, Content of Dichloromethane  & Assay, and microbial limit. Storage Environment Temperature: Below 30ºC Protect from light and moisture Microbial Limit: Refer to GTP for microbial limit testing as per USP Microbial Limit: Total aerobic microbial count: NMT 500 cfu per g Total combined molds and yeast count: NMT 50cfu per g Escherichia coli: Should be absent Salmonella species: Should be absent Pseudomonas aeruginosa: Should be absent Staphylococcus aureus: Should be absent  Test Method Description, identification, Average weight,  Disintegration, Dissolution, Single highest impurity, total impurities, Content of Dichloromethane  & Assay: Refer to STP. Acceptance Criteria Description: Blue /Transparent Hard gelatin capsules, size “00” LOGO in white color ink containing red, white Blue & yellow beads. Identification: A. By HPLC: The retention time of Dextromethorphan Hydrobromide, Chlorpheniramine Maleate & Phenylephrine Hydrochloride the major peak in the chromatogram  of the test preparation corresponds to that in the chromatogram of the standard preparation, as obtained in the assay. B. By TLC: Paracetamol, the principal spot in the chromatogram obtained with solution (1) corresponds to the solution in the chromatogram obtained with solution (2) Uniformity of fill weight:  Not more than two of 20 individual weights deviate from the average weight by more than 7.5%  and none deviate by more than 15.0%. Disintegration time:    Not more than 30 minutes Dissolution: Not less than  75% of the labeled amount dissolves in 45 minutes    Impurities:    Complies With The Test Single highest impurity:Not More Than 1.0% Total impurities: Not More Than 2.0% Content of Dichloromethane:  Not More Than 0.05% Assay: Each capsule contains :  (a) Not less than 95.0% and not more than 105.0 % (14.25 mg to 15.75 mg) of the label claim of  Dextromethorphan Hydrobromide BP, C18H25NO, HBr(15 mg). (b) Not less than 95.0% and not more than 105.0 % (1.9 mg to 2.1mg), of the label claim of Chlorpheniramine Maleate BP, C16H19CIN2, C4H4O 4 (2mg). (c Not less than 95.0% and not more than 105.0 % (9.5 mg to 10.5 mg) of the label claim of  Phenylephrine HydroChloride BP, C9H13NO2, HCl (10 mg). (d) Each capsule contains not less than 95.0% and not more than 105.0 % (475.0 mg to 575.0 mg)of the label claim of  Paracetamol BP, C8H9NO2, (500 mg).

Revalidation

If required, revalidation is  carried out when any of the following conditions occur or prevail:

Change in critical formulation component i.e. raw material

• Change in manufacturer or vendor of Active Pharmaceutical Ingredient
• Change in critical specifications of the product
• Changes in the manufacturing process may affect the quality of the products.
• Change in the facility and /or plant (location or site)
• Change in batch size, if more than ten times the present batch size

Note:  In case of the requirements for revalidation, because of above mentioned reasons, the validation of the critical steps shall be undertaken through an addendum attached to this protocol. 

OOSs and Investigations

Any out-of-specification test results shall be recorded as per SOP.

Validation Report

Based on the outcome of this validation study, a report shall be prepared by Quality Assurance persons. This validation report shall be reviewed and then approved by all functional heads of all the concerned departments.

Reference Documents

1. In-process Specifications & Finished Product Specification & GTPs.
2. British Pharmacopeia
3. Master Formula
4. Raw Material Specifications
5. Batch Manufacturing Records
6. Batch Packing Records
7. Equipment Qualification Documents
8. Instrument Calibration Records
9. Process and Finished Product Specifications

List of Annexures / Formats Attached

Validation team  members

Equipment list

Approved raw materials list

Critical process variables

Sampling plan and analytical data compilation for blending

Drug layering ingredients

Sampling plan for drying

Differential screening

Final Blending

Sampling plan and analytical data compilation for capsule filling

Sampling plan and analytical data compilation for holding studies

Process validation report cover page

Process validation report approval sheet

Process validation report.

Air Filtration by Membrane AS PER USFDA GUIDELINE