Stage 3 - Process Validation: Measuring what matters

Transcription

1 Stage 3 - Process Validation: Measuring what matters Trevor Schoerie - PharmOut

2 A quote. The company that fails is the company that comes to us and says Just tell us what to do and we will do it. The company that succeeds is the company that says to us Here is what we did and why we think it is appropriate. Dr. Phillip Minor National Institute of Biological Standards and Control A science and risk based approach

3 What the current GMPs say PIC/S, EU GMPs 1.1 v. all necessary controls on intermediate products, and any other in process controls and validations are carried out. CFR (a) Sampling and testing of in-process materials and drug products. To assure batch uniformity in-process materials. Such control procedures shall monitor the output and to validate responsible for causing variability

4 What the current GMPs say EU/PIC/S 1.2 ii. critical steps of manufacturing processes and significant changes to the process are validated; 1.2 iii. all necessary facilities for GMP are provided including: a. appropriately qualified and trained personnel; people* b. adequate premises and space; environment* c. suitable equipment and services; machines* d. correct materials, containers and labels; materials* e. approved procedures and instructions; methods* f. Suitable storage and transport; *fishbone (+measurements)

5 What the current GMPs say - FDA CFR (a). such control procedures shall include, but are not limited to, the following, where appropriate: 1. Tablet or capsule weight variation; 2. Disintegration time; 3. Adequacy of mixing to assure uniformity and homogeneity; 4. Dissolution time and rate; 5. Clarity, completeness, or ph of solutions.

6 FDA Process Validation? Lifecycle concept, but QbD is at the start of the product lifecycle, i.e. product design, R&D FDA Process Validation - 3 stages 1. Process Design (QbD & DOE) 2. Process Qualification 3. Continued Process Verification

7 EU GMP Guide Annex 15 Qualification & Validation Concurrent Validation May be acceptable in exceptional circumstances "where there is a strong risk benefit to the patient" Traditional Approach Produce a number of batches under routine conditions, confirming reproducibility Continuous Process Verification Science-based control strategy Hybrid Approach The Traditional Approach and Continuous Process Verification together

8 EU GMP Guide Annex 15 Qualification & Validation Design Space

9 What is the goal? Focus of FDA Process Validation Guideline Variable or variability - Mentioned 19 times Control - Mentioned 62 times Statistics - Mentioned 15 times Inputs and Outputs Fishbone Model

10 FDA (& EU) Process Validation Stages Stage 1 Process Design: The process is defined during this stage based on knowledge gained through development and scale-up activities. Identify sources of Variability Stage 2 Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. Control of Variability Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control. Monitoring Variability - remains in control

11 Lifecycle Process Design PV (PPQ) Commercial Manufacturing Level of QC Lab Testing Could vary based on approach Variability Estimate Established Post Periodic Review Signal Change introduced / CAPA PAT Implemented Monitoring QC Testing Time / Product & Process Knowledge Control Strategy is dynamic over the lifecycle

12 3 Stages - Generic Acetriptan Tablets Stage 1 Define the Quality Target Product Profile (QTPP) Identify the CQAs Define Process Steps & CPPs Create a Control Strategy Stage 2 Implement the Control Strategy Qualify Facility, Utilities, Systems and Equipment Process Validation (PPQ) Stage 3 Continued Process Verification Science and Risk-based Approach at all Stages of Lifecycle

13 Quality Risk Management (QRM) Begin the QRM Process Risk Assessment Risk Identification Risk Analysis Product & Process Development Risk Evaluation Risk Communication Risk Control Risk Reduction Risk Acceptance QRM Tools Output of the QRM Process Risk Review Review Events ICH Q9

14 Initial RA of the formulation variables DP CQAs Assay Content Uniformity Dissolution Drug Substance PSD MCC/ Lactose Ratio CCS Level Talc Level Mag. Stearate Level Medium Medium Low Low Low High High Low Low Low High Medium High Low High Degradation Products Low Low Low Low Medium High Medium Low Risk is unacceptable. Further investigation is needed to reduce the risk. Risk is acceptable. Further investigation may be needed in order to reduce the risk. Broadly acceptable risk. No further investigation is needed.

15 Design of Experiments (DoE) A designed experiment allows understanding of how input variables are related to output variables Input Process Output Experimental units are units to which one treatment is assigned or applied Input variables are called factors-controlled independent variables whose levels are set by the experimenter Levels of a factor are the settings that are tested in an experiment

16 Defining CPPs Process Variable Can variable be controlled? NO Process Performance Attribute OR Product Quality Attribute YES Process Input Potentially a CPP YES Potential Impact to CQAs? NO Potentially NOT a CPP Critical Process Parameter YES Risk Assessment. CPP? NO Key Process Parameter OR Non-Key Process Parameter

17 Equipment & fixed process parameters used in the formulation studies Process Step Pre-Roller Compaction Blending and Lubrication Roller Compaction and Integrated Milling Final Blending and Lubrication Tablet Compression Equipment 4 qt V-blender 250 revolutions for blending (10 min at 25 rpm) Alexanderwerk WP120 with 25 mm roller width and 120 mm roller diameter Roller surface: Knurled Roller pressure: 50 bar Roller gap: 2 mm Roller speed: 8 rpm Mill speed: 60 rpm Coarse screen orifice size: 2.0 mm Mill screen orifice size: 1.0 mm 4 qt V-blender 100 revolutions for granule and talc blending (4 min at 25 rpm) 75 revolutions for lubrication (3 min at 25 rpm) 16-station rotary press (2 stations used) 8 mm standard round concave tools Press speed: 20 rpm Compression force: 5-15 kn Pre-compression force: 1 kn

18 Tablet Compression Process Development Effect of Main Compression Force, Press Speed and Ribbon Relative Density: Compression force and press speed (related to dwell time) can affect numerous quality attributes including hardness, disintegration, dissolution, assay, content uniformity, friability, weight variability & appearance. The density of the ribbon following roller compaction may also impact the compressibility and compactability of the granules which would then impact tablet hardness & dissolution.

19 Tablet Compression Process Development A 2 3 full factorial DoE with three centre points was performed to understand the effects of these parameters on tablet quality attributes Factors: Formulation Variables Levels A Main compression force (kn) B Press Speed (rpm) C Ribbon relative density (no units) The press was run at the speed of the specified DOE for at least five minutes prior to any sampling. Tablet samples were then pulled at the beginning, middle and end of each run (except one Batch which was sampled every 20 min).

20 Tablet Compression Process Development The results obtained from the development work identify acceptable ranges Feeder frame paddle speed (8-20rpm) Press speed (20-60rpm) The data also allows potential In-Process Controls to be identified for the compression step: Test Frequency Limits Individual tablet weight (n =10) 30 min mg ± 10.0 mg Composite tablet weight (n =20) 30 min 4.00 g ± 0.12 g Hardness (n = 10) 30 min Target: kp Limits: kp Thickness (n = 10) 30 min 3.00 mm ± 0.09 mm Disintegration* (n = 6) 3 x per run NMT 5 min Friability* (sample weight = 6.5 g) 3 x per run NMT 1.0%

21 Scale-Up from Lab to Pilot Scale and Commercial Scale Scale-up information is usually limited at the time of submission. The principles of scale-up should be detailed as part of a planned approach. It is the firm s discretion to submit scale-up data such as actual process verification information at the time of submission for a complex drug product which has a high risk of scale-up failure. Scale Batch Size Units Development (Lab) 5Kg 25,000 Pilot (Exhibit) 50Kg 250,000 Commercial (Proposed) 150Kg 750,000

22 Scale-Up of the Roller Compaction & Integrated Milling Process Several process parameters to consider when scaling up to a larger, wider roller. The strategy employed should be documented. Roller Gap, Roll Force or Roll Pressure Screw Speed and Roll Speed Mill Screen Size and Mill Speed Scale Model Roller width (mm) Roller diameter (mm) Roller Gap (mm) Roller Pressure (bar) Mill screen orifice (mm) Lab WP Pilot WP Commercial WP

23 Initial Risk Assessment of the Manufacturing Process High risks identified during development Scientific knowledge & understanding gained Appropriate controls developed to reduce risk to an acceptable level documented DP CQAs Assay Content Uniformity Dissolution Pre-RC Blending & Lubrication Roller Compaction Milling Final Blending & Lubrication Compression Low Low* Low Low* Low Low Low Low Low* Low Low Low Low Low Low Degradation Products Low* Low* Low* Low* Low* *The level of risk was not reduced from the initial risk assessment

24 Other items for consideration Container Closure system: Round white opaque HDPE bottles with an induction seal liner and child resistant (CR) closure Labelled for storage at 25 C with excursions permitted to C Microbiological Attributes: An accelerated stability study of the exhibit batch demonstrated that the drug product has low water activity and is not capable of supporting microbial growth. Routine testing of tablets unnecessary

25 Control Strategy Built up based on previous knowledge and the outcome of extensive product & process studies Investigation of material attributes and process parameters that were deemed high risk to the CQAs of the DP during initial risk assessment Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs) were determined Acceptable Operating Ranges were identified All variables that were deemed high risk are included in the control strategy Can be further refined as process knowledge increases over time Create a Control Strategy

26 Quality Risk Management (QRM) Begin the QRM Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Communication Risk Control Risk Reduction Risk Acceptance QRM Tools Control Strategy Development Output of the QRM Process Risk Review Review Events ICH Q9

27 Control Strategy Examples Factor Acetriptan particle size distribution* Talc, Grade D04 Attributes or Parameters Range Studied Actual data for the exhibit batch Raw Material Attributes Proposed range for commercial scale Purpose of control d μm 20 μm μm To ensure in d μm 12 μm 6-24 μm vitro dissolution, d μm 7.2 μm μm in vivo performance and batchto-batch consistency Particle size distribution > 75μm: NMT 0.2% > 75μm: 0.1% >75μm: NMT 0.2% To ensure batch-tobatch consistency *Critical input Material Attributes (CMA)

28 Control Strategy Examples Factor Blend uniformity* Rotary press Attributes or Parameters Range Studied Actual data for the exhibit batch Proposed range for commercial scale Pre-Roller Compaction Blending and Lubrication In-Process Controls Blend to endpoint: < 5.0% RSD (In-line NIR method) Tablet Compression Process Parameters Feeder frame paddle speed Purpose of control In-line NIR method is used for endpoint determination to ensure BU is met consistently 8-20 rpm 15 rpm 8-20 rpm To ensure all tablet CQAs are met consistently *critical process parameter (CPP)

29 Stage 2 Process Qualification Demonstrate that the process is capable of reproducible commercial manufacture It should be completed before product is released commercially Two parts to this Stage: Design & Qualification of FSE Process Performance Qualification Product that meets predetermined quality attributes

30 Process Validation Demonstrates the validity of the process design and the suitability of the process control strategy At full-scale (commercial manufacture) Provides confidence (documented evidence) that systems of monitoring, control and SOPs in production are capable of detecting and compensating for potential sources of process variability over the product lifecycle The number of PV batches to be produced should be justified

31 Knowledge vs # of PV batches Limited Prior Knowledge may require more PV batches Prior Knowledge Process Design PV Comprehensive Prior Knowledge may support fewer PV batches Prior Knowledge Process Design PV

32 Stage 3 (a) and (b) How many PPQ batches? This depends on the risk and the following elements could be applied to make the decision: Rationale and experience-based justifications Based on Target Process Confidence and Target Process Capability Based on expected coverage

33 Quality Risk Management (QRM) Begin the QRM Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation Risk Communication Risk Control Risk Reduction Risk Acceptance QRM Tools Output of the QRM Process Risk Review Review Events Continual Improvement ICH Q9

34 Maintenance of the Validated State Continued Process Verification Change in the validated state of the process could impact product Monitored via: Change Control Periodic Monitoring Data Trending Review Calibration and PM Knowledge of operational parameters (Control Strategy) and Design Space (if applicable)

35 Thank you for your time. Questions? Trevor Schoerie Executive Consultant