Pharmaceutical control strategy what does it mean and how do we apply? Martin Warman, Martin Warman Consultancy Ltd

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1 Pharmaceutical control strategy what does it mean and how do we apply? Martin Warman, Martin Warman Consultancy Ltd

2 How can the words control strategy cause such debate? Means totally different things to different audiences A automation engineer regards the control strategy as the actions taken by the process control system control system, n system that responds to inputs signals from the process, its associated equipment, other programmable systems or an operator or both, and generates output signals causing the process and its associated equipment to operate in the desired manner. (Perry s Handbook of Chemical Engineering ), but also referenced in ASTM E Standard Terminology Relating to Process Analytical Technology in the Pharmaceutical Industry However from a product quality viewpoint control strategy, n a planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. ICH Q10

3 Objective of this presentation? To get each side to understand that both are correct! More so, going forward the two ends of the spectrum will be shown to be a continuum Especially as we move towards advanced manufacturing/industry4.0 But first we have to do a deeper dive into the world of (performance based) control strategy

4 What is a performance based control strategy? ICH Q8 (R2), section 2.5 A control strategy is designed to ensure that a product of required quality will be produced consistently. The elements of the control strategy discussed in Section P.2 of the dossier should describe and justify how in-process controls and the controls of input materials (drug substance and excipients), intermediates (in-process materials), container closure system, and drug products contribute to the final product quality. These controls should be based on product, formulation and process understanding and should include, at a minimum, control of the critical process parameters and material attributes.

5 A control strategy can include (but is not limited to..) Control of input material attributes (e.g., drug substance, excipients, primary packaging materials) based on an understanding of their impact on processability or product quality Product specification(s) Controls for unit operations that have an impact on downstream processing or product quality (e.g., the impact of drying on degradation, particle size distribution of the granulate on dissolution) In-process or real-time release testing in lieu of end-product testing (e.g. measurement and control of CQAs during processing) A monitoring program (e.g., full product testing at regular intervals) for verifying multivariate prediction models.

6 Not all control strategies are equal FDA Complexity Pyramid First published in the AAPS Journal Vol 16, Number 4, July 2014 Included in the paper, Modernizing Pharmaceutical Manufacturing: From Batch to Continuous Production Journal of Pharmaceutical Innovation, Vol 10, Issue 3, Sept 2015

7 Level 3 control strategy recipe control Relies on tightly constrained material attributes and process parameters. There may be limited understanding on how raw material and process variability affects product quality. The risk of releasing poor quality product is lowered through extensive end-product testing. NB looking forward the FDA view point is Level 3 control is generally not feasible for many continuous manufacturing (CM) process designs Because of the risk of potential transient process disturbances

8 Time for an analogy - 10 pin bowling Level 3 control strategy is like using a bowling ramp The ramp is aimed in the same direction as previously hit the pins Assumes nothing changes as the bowl rolls towards the pins Measure success by the number of pins hit The main metric of state of control is when the ball arrives at destination If the outcome is not as expected you have no-idea why, and so don t have the ability to aim better next time

9 Level 2 control strategy pharmaceutical control Consists of pharmaceutical control with appropriate end-product testing and flexible raw material attributes and process parameters within the established design space (the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality). There is a requirement to have developed a design space The product and process understanding obtained through the establishment of a multivariate design space facilitates the identification of potential sources of raw material and process variability that can impact product quality. Product release based on design space, ie has been filled Understanding the impact that variability from these sources has on in-process materials, downstream processing, and drug product quality provides an opportunity to shift controls upstream and to reduce the reliance on end-product testing Product release based on the process remaining with a state of control

10 Back to the analogy Level 2 control strategy is like bowling with bumpers The objective is to hit the pins Not which pin to hit The bumpers ensure the ball does not go in the gulley The ball is nudged back into the design space if it starts to deviate Material made outside design space is segregated Keep track of the number of times the bumper was hit, and control strategy includes a no more than (NMT) statement around number of bumps to demonstrate the process stayed in a state of control

11 Level 1 control strategy engineering control Utilizes an active process control system to monitor the quality attributes of materials in real-time. Process parameters are automatically adjusted in response to disturbances to ensure that the quality attributes consistently conform to the established acceptance criteria. This level of control represents a high degree of product and process understanding as the design of an engineering control system entails expressing the dynamic relationships among process parameters, raw material and product attributes in a quantitative and predictive manner. The risk of producing out-of-specification product is lowered through the implementation of adaptive engineering controls which can enable a real-time release strategy.

12 Back to the analogy Level 1 control strategy requires Understanding the process of bowling and the factors that influence the direction the ball takes Measuring the progress of the ball Having the ability to change the direction Having an target to hit The objective is not to just to hit pins The trajectory travelled decides if the process has run as expected Accumulation of date as the process as run is used to decide if the target has been reached Of course if you want to also look at the number of pins that are down, no one will mind!!!!

13 State of control applies to all levels State of control is a condition in which a set of controls consistently provides assurance of continued process performance and product quality. A process operating under a state of control helps to ensure that product with the desired quality is being consistently manufactured. A state of control could differ from steady state where all the parameters and material attributes associated with the process do not vary with time. Criteria for the establishment of a state of control depend upon the control strategy employed.

14 Is level 1 achievable? Incivek Use Case often referenced in FDA presentations

15 What is (was) Incivek? Telaprevir (VX-950) was marketed under the brand names Incivek and Incivo For the treatment of hepatitis C Developed by Vertex Pharmaceuticals Licensed to Johnson & Johnson for sales in Europe Member of a class of antiviral drugs known as protease inhibitors Telaprevir inhibits the hepatitis C viral enzyme NS3.4A serine protease Telaprevir molecule which has the solubility of marble, is often given as an example of the first fully Quality by Design (QbD) submission Batch process with continuous processing steps Complex synthesis Spray dried dispersion (SDD) Blending Compression Tablet coating (non-functional)

16 QbD development: critical process steps identified 1 6

17 Three dimensional design space 1 7

18 Huge spray drying database generated during development

19 Control models Identified using regression analysis; particle size 19

20 Control models identified using regression analysis; bulk density 20

21 HMI visualization Dashboard sits on plant control system showing Design space ranges NOR Real-time indicator of CQA predictions from parametric data 2 1

22 What does this all look like together? 2 2

23 How do we know this works? 23

24 Filled process Allows the required disso performance to be set The SDD process operated at the required process conditions to generate the particle size and bulk density required to generated the SDD particles required Under feedback control so if the IPC shows either PS or BD were not as required the process conditions could be changed to correct Feedforward control Press compression settings (recipe parameters) selected based on achieved PS and BD to give the disso performance required It is a Level 1 filing

25 Routine operation Even though the design space allows freedom to move the process and during process development and process qualification the process was driven In routine production it was run as a Level 2 process and state of control = staying inside PAR Always made acceptable product Never used to make a product with specific attributes even though it could Why not run as a Level 1 process? Why when a Level 2 gives 100% acceptable product?????????

26 Challenges going forward It doesn t matter if we approach from a viewpoint of performance based control strategy or process control (including advanced process control/model based control), there needs to be a driver for that control If the process stays in a state of control and can be shown to make acceptable product using recipe control, why move to a paradigm of pharmaceutical control? Because, some of our processes have low process capabilities, generate non-conforming products Find out if there is a need first! Pharmaceutical control/qbd was introduced to ensure product quality It does give more freedom to adjust the process if needed Too often the action limits/triggers are used to determine material for segregation, whilst in parallel a change made to setpoint Why? A set-point change has to be made in a way that the process moves from its current process point to the new set-point without compromising the process further The validation burden of this sort of step change is significant, would be far better making smaller, more regular change level 1 control Because challenge as we move to a environment based on holistic control, is we have to change the mind-set from level 3 is OK, level 2 prevents OOS, to using level 3 (or APC/MBC) means we don t have to worry if the product is OK and we can t make OOS material this is a significant mind-set change!

27 Conclusions State of Control means different things at different levels on the complexity pyramid Need to define upfront which level you are trying to operate at Most QbD development is aimed at Level 1 but run at Level 2 In theory you could aim at Level 2 to demonstrate a robust process the operate at level 3 No-one has successfully achieved that, but that doesn t mean it isn t possible! Final thought If making control decisions using process analytics/parametric data you need a strategy for ensuring that data is appropriate (redundancy, parallel testing etc), is carried out under an appropriate quality system, the methods are appropriately validated, and you have a strategy for life-cycle maintenance..having the ability to predict a value or trend a process is just the first step.

28 Thankyou for your attention Questions?