Professional Documents
Culture Documents
Part I
by Pramote Cholayudth GPO, BIOLAB & VALITECH Tel 0-1932-2374 Email: cpramote2000@yahoo.com
August 22, 2006
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Learning Objectives
To review the Process Validation Rationale To learn about the Process Validation Practices in pharmaceutical industry To review the critical process parameters (CPP) for Solid Dosage Forms To learn about establishing Sampling Plan and Acceptance Criteria To learn about the Process Validation Protocol requirements
Scope of Presentation
Execute protocols Write protocols Develop procedure & specifications Define process & equipment Collect & interpret data Prepare summary reports Review & approve reports Change & Change Control
Protocol Outline Objective Scope Rationale Personnel Responsibilities Process Description Process Flow Chart Equipment (Process/Lab) Sampling Plan Acceptance Criteria
PIC/S EMEA
EU
WHO
Original is kept; One photocopy for one batch is used by hand-writing with final approval
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Protocol Requirements
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Objective
To validate the manufacturing process of ProMed Tablets 2 mg, Enteric Film Coated, through demonstrating that
critical process parameters are controlled within the process limits critical product parameter data consistently & reproducibly meet the specifications using appropriate challenging conditions
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Scope
This protocol is applied to ProMed Tablets 2 mg, Enteric Film Coated, batch size 500,000 tablets, BPR # 001, manufactured in ProMed Pharma Plant, Suwannaphume. Execution of this protocol is planned in September 2006
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Rationale Transfer
PV Rationale
Critical steps are validated Critical process parameters and limits must be identified The process when operated within the process limits performs as intended The process does perform consistently as intended
PV Protocol Rationale
Define critical steps to validate Define critical process parameters and their limits Demonstrate that critical product data meet the specifications (an experiment) Demonstrate that critical product data consistently meet the specifications
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PV Protocol Rationale
Critical steps are defined and validated Critical process parameters are defined and demonstrated to be within the process limits Upon challenging the critical process parameters, the critical product parameter data always meet the specifications (separate trial) Using the CPPs in BPR, the critical product data consistently meet the specifications
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Process Description
Components of wet mass are dry-mixed in High Speed Mixer/Granulator. After addition of granulating liquid, the mixture is kneaded until a suitable granulation is obtained, then sieved through High Speed Granulator (4.0 mm). The granulation is dried in Drying Oven at 50 C until loss on drying (LOD) limit of 1.0-2.0 % is met, then sieved through High Speed Granulator (1.0 mm).
The API is moisture sensitive and will partially degrade upon moisture uptake.
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Process Description
Disintegrant and lubricant are sieved through 0.5 mm, add the first one and blend with the granules in V-Shape Blender to obtain a uniform blend and finally add the latter and blend further until the final blend is uniform. The final blend is compressed into tablets using rotary tablet compression machine. The core tablets are finally enteric film-coated using Film-Coating Machine.
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Quality Attributes Challenge IPC N/A API 3 lots API diff lots PV Challenge study RM Sieving IPC Appearance Sieve # (HS Gran) PV Follow IPC CPP should be specified e.g. temp = 50C, time = 30 min.
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Quality Attributes IPC Appearance PV Blend uniformity IPC Damp massing PV Follow IPC
Mfg Steps
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QC sampling included
Responsibility WHO
Several possible methods of organizing validation are available, one of which is the establishment of a validation group. The management appoints a person responsible for validation (validation officer), who then forms the group (team, committee). This is headed by a group leader, and represents all major departments: development, production, engineering, quality assurance and control. The composition of the group should be changed from time to time to give opportunities to other people to generate new ideas and to gain experience.
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Responsibility
Validation Coordinator is responsible for (1) providing this validation protocol, (2) ensuring the overall validation is in accordance with the protocol (3) collecting all the analytical results and all the validation batchs IPC data, (4) conclusion of the validation test results and (5) generating Validation Report for each validation batch and Validation Final Report for the three validation batches to be approved by the authorized Validation Team members.
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Responsibility
Quality Control (QC) is responsible for performing the chemical, physical, and microbiological analyses and supplying all the analytical results to the Validation Coordinator. Production, in coordination with QC and Validation Coordinator, is responsible for scheduling the validation batches and for taking, labeling, and submitting the validation samples to the Quality Control laboratory.
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Equipment Used
Mfg Steps Sieving Wet Granulation Drying Blending Compression Metal Detection Homogenization Film coating Equipment HS Granulator HS Mixer/Gran Drying Oven V-Shape Blender Tableting Machine Metal Detector Homogenizer Film Coater Brand/Model PMS PMS/100 kg SSS/100 kg PMS/100 kg NR/NRT 25 Lock Local PMS
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Equipment Used
IPC Testing LOD Tablet Weights Tablet Hardness Disint Time Friability Equipment Moisture Balance Top Load Balance Hardness Tester Disint Apparatus Friabilator Brand/Model MT/LP 16 MT/AX204 Erweka/TBH20 PT/PTZ3 PT/PTFR4
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Mfg Steps Active Ingredient RMs Sieving Premixing (before Wet Granulation)
CPPs Particle Size Different lots Mesh # Type of machine Mixing time Mixing speed Mixing volume Mixing method
Impact on Quality Product dissolution Challenge study Breaking lump Foreign mat potential Blend uniformity
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Wet Granulation
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Tableting
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Wet Granulation
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QC Testing
Spec
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Pre-Mixing
Blend Uniformity see Blend Uniformity Acceptance Criteria for Final Blending
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Drying
Loss on Drying (LOD): The Acceptance Criterion is based production specification for LOD Take at least 3 samples (10 g each) from three different locations throughout the oven chamber
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Final Blending
Critical Quality Attributes (CQAs) are as follows: Blend Uniformity Size Distribution (Sieve Analysis) % Compressibility Loss on Drying (LOD) Maximum Hold Time
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Product Parameters
Target (Theory) 10
24.87 10 24.07
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(www.ikev.org/haber/bozzone/may31.pdf)
V-Shape Blender
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(www.ikev.org/haber/bozzone/may31.pdf)
Bin Blender
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Uncoated WV Content Uniformity (CU) Film Coat Content Uniformity (CU) Other Coat WV Hard Cap Content Uniformity (CU) In USP 27 or earlier, 50 is used in place of 25 mg and %
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F0.9,n1 ,n2 =
2 S1 2 S2
S=
6 F0.9,9,n1
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SD =
6 F0.1,9,n1
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There is 95% confidence that future test results will fall within mean 10% (absolute)
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x x xx x x xx x x x LSL & USL = Lower & Upper Specification Limits LPL & UPL = Lower & Upper Prediction Limits = Sample mean k.SD
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Comparison of SD Limits
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Additive Contents
Additive contents e.g. preservative, wetting agent, antioxidant, or chelating agent, should be determined in process validation (if possible) A capsule product containing wetting agent has a problem of dissolution rate (DR) fluctuation poor distribution of the agent Verification of admixing method is required
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(www.ikev.org/haber/bozzone/may31.pdf)
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(www.ikev.org/haber/bozzone/may31.pdf)
Scale-Up of Blending
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Lower Extreme
30 20
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0 0 5 10 15 20 25 Time (min) 30 35 40 45 50
Tableting
Critical Quality Attributes (CQAs) are as follows: Content Uniformity Assay Dissolution Rate
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= Fall within, = Fall outside (1) Location mean of 3s (TA = Target Amount) Sampling Plan: 10 x 7s, Testing Plan: 10 x 3s
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NMT c units 85 Means 90 Content 115% LA, all units 110% TA Uniformity (CU): 75 125% LA n = 30 RSD 4.8% RSD 4.8% c = 1 for tablets; c = 3 for capsules Sampling Plan: 10 x 7s, Testing Plan: 10 x 3s
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NMT c units 85 Means 90 Content 115% LA, all units 110% TA Uniformity (CU): 75 125% LA n = 70 RSD 5.4% RSD 5.4% c = 1 for tablets; c = 3 for capsules Testing Plan: 10 x 4s; Evaluating: 10 x 7s
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NMT c units 85 Means 90 115% LA, all units Content 110% TA Uniformity (CU) 75 125% LA RSD P% RSD P% c = 1 for tablets; c = 3 for capsules (for both stages) Stage 1: n = 30, P = 4.8; Stage 2: n = 70, P = 5.4 Sampling Plan: 10 x 7s, Testing Plan: 10 x 3s, 10 x 4s
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10.1/10 = 101% LA 10.1 119 8.49 8.49/8.33 = CU WC Data 101.92% TA % Target Amount (% TA) = % Target Potency (% TP)
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0 unit 1 unit 2 units 3 units 30 54.5 33.4 1 Tablets 70 24.3 34.7 2 30 54.5 33.4 9.9 1.9 1 Capsule 70 24.3 34.7 24.5 11.3 2 This is in case of RSD = 4.8% (n = 30) or 5.4% (n = 70) For RSD < ABOVE, Probability for zero unit is increased
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Stage #
PDA Technical Report # 25: Blend Uniformity Analysis: Validation and InProcess Testing, October 1997
To be purchased from www.pda.org
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USP 28: If Val. RSD 2%, no CU test but WV is required, cancelled in USP 29
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