Continuous Manufacturing Control Strategy

Martin Warman, Martin Warman Consultancy Ltd

Pharmaceutical control strategy is NOT……..

• About “Advances in Process Analytics and Control Technology” in the conventional sense• But please bear with me!

• So not……• Recipe control/automation

• Model/advanced process control

• So what is Pharmaceutical Control Strategy??????????

What is a pharmaceutical control strategy?

• It is a planned set of controls, derived from current product and process understanding, that assures process performance and product quality (ICH Q10)• Assures process performance, and assures “product” quality

• Not necessarily meaning “end product”, it means the output of that manufacturing operation

• In batch-wise manufacturing this is easy to define• Operation stays within bounds• Output quality verified either during or after the operation

• Samples/data acquired to determine output quality are called In Process Controls (IPC)

• But even in batch-wise manufacturing there is the control strategy complexity pyramid

Control strategy complexity pyramid

• 3 levels of control strategy• Recipe control – level 3

• Process run against set points (staying within a delta of the set points)• Product quality tested during processing (IPC)• End-line testing for product release

• Pharmaceutical control – level 2• Design Space (DSp) model• Ensure the process stays in a state-of-control

• Using defined acceptance limits for Critical Process Parameters (CPP), Critical Material Attributes, and IPC

• Accumulation of the CPP, CMA and IPC data replaces end-of-line testing for real-time release

• By predicting Critical Quality Attributes (CQA)

• Engineering control – level 1• DSp but also control models that allow the process to be driven to a

specific process space with DSp• CPP, CMA, IPC are all inputs to control models

• Process models link intermediate CQA to final CQA so control decisions can be made to not only ensure compliance of material produced

• Generate material of a specific quality.

Most common approach - Level 2

• Design space developed in process development phase• Critical Process Parameters (CPP) identified

• Normal operating range specified for all CPP• DSp model (normally multivariate) to predict product quality• In-process control (IPC) shows process is proceeding as expected

• CPP, DSp and IPC show the process is in a state-of-control• Action limits set to ensure product does not go out of range

• Actions can include, material segregation and adjustment of set-points (within approved design space)

• Action limits are not necessarily ‘acceptable ranges’• Action limits can be set within acceptable ranges to trigger a control action before

the acceptance limit is crossed• But there is often no action taken if the process stays in a state-of-control

Batch-wise control strategy exampleTelaprevir

Telaprevir

• Telaprevir (VX-950) was marketed under the brand names Incivek and Incivo• 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)

• The two critical process steps (SDD and compression) run continuously

Three dimensional DSp

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• Frequency of IPC determination set based on process dynamics

• Feedforward control• Press compression settings (recipe parameters) selected based on achieved

PS and BD to give the disso performance required

• It was an approved level 1 filing

Routine operation

• Even though the design space allows freedom to move the process and during process development• During process validation the

process was ‘driven’ across DSprange

• In routine production it was run as a level 2 process• State of control = staying inside

PAR• Always made acceptable product

• Why not run as a level 1 process?• Why when a level 2 gives 100%

acceptable product?????????

What about continuous manufacturing (CM) processes?Process Dynamics

CM process dynamics

• Not all CM processes have the same process dynamics• Can not generalize!

• More so, there is process dynamics within a unit operation• E.g. in a continuous (conti) blender vs a mini-batch blender (MBB)

• But also during material transfers• E.g. during conveying (especially pneumatic), which is particularly good at ‘rank

ordering’ material based on flow properties• But also during feeding, when existing material is mixed with new material each time

the feeder is topped up

• This is not always immediately apparent• E.g. a tablet press feed frame can be a good mixer if using a ribbon (spaghetti) paddle

or act more like a CSTR if you use a star paddle

Batch-wise vs CM control strategy

• Batch-wise, we can use a Level 3 approach because• The entire mass of the batch under goes the process transformation at the

same time• Focus is on heterogeneity/uniformity within the batch

• For CM the only inter-mixing that occurs is that induced by the process dynamics• Although there is inter-mixing in a conti blender the degree of intermixing is

characterized by the residence time (RT) and more specifically the residence time distribution (RTD)

• But if mini-batch blending (MBB) is used then RTD is fixed (it is the mass of material in the blender, the same as batch-wise blending)

A word about MMB

• Does a car engine have a continuous output?• Yes

• Is the combustion process MMB• Yes

• MMB can be part of a CM process

Blenders used in CM lines

• Not all the same!• Conti blenders (blue line)

• Have a mean residence time higher than the line rate• Intermixing delays material as it passes• Good candidates for using RTD to justify control

strategy

• CMT blenders (red line)• Have a mean residence time almost equivalent to

line rate• Instantaneous mixing• Long dragged out tail• Broad RTD but not symmetrical• Also shown to have issues with regard lubrication

(especially MgSt)• Narrow range of HuM x tip speed can be

used

• MBB (dotted line)• Used initially then fell out of favor• Being re-introduced to achieve low volume line rates

• Batch addition, batch mixing, repeat

Impact on control strategy?

• IPC (often PAT) methods have to have a scrutiny of scale to represent CQA• E.g. a blend assay system has to measure at a unit dose scale

• Whether the PAT method is a soft-sensor (prediction based on process data) or measurement (prediction based on spectroscopic data)

• IPC frequency has to measure at a rate capable of seeing the process variance (both short-term and long-term)• But variance can be impacted by process dynamics

• Process dynamics drives frequency at which control actions are applied• Conti blenders have RTD to smooth output but take longer to reach a state of control

due to residence volume• MBB have ni intermixing between ‘mini-batches’ and so each ‘min-batch needs to be

verified• But verification can be gravimetric because we ‘weigh-in’ and ‘weigh-out’

Visualization of application of control strategy

Sampling plan for In Process Controls

• Sampling plan should be defined for each IPC• Minimum sampling that must be met for each IPC should

be defined and statistically justified

• Actual IPC sampling achieved

• CM does not facilitate reprocessing• Non-conformance to IPC acceptance criteria results in removal of the material from the process

• Therefore any control actions limits have to be set withinthe IPC acceptance limit range to ensure that IPC acceptance criteria are met

Where to set IPC action limits

• Action Limits:

• Set inside the IPC limits• Driven by the precision of the method

• With a threshold equivalent to No Less Than (NLT) step change• Ensures the process remains in control and that non-conforming materials are identified with NLT a

defined confidence limit confidence

What is a NLT limit

• Limit set to ensure the sampling criteria has been met• This can be a combination of procedural controls

and automated processes• Impacted material should be processed to a

segregation point and removed from the process

• Procedures should be in place to investigate the event and evaluate the impacted material

• If IPC data is ‘missing’ (e.g. if a spectrometer is re-referencing at that moment), we do not have a measure of quality

• Can use tools like lag k difference analysis to determine whether or not the material would conform to the IPC acceptance criteria• Within confidence limits

PAT methods for blend/tablet cores

• Need to select an approach that fits the process dynamics

• E.g. if using feeder data to predict assay and uniformity• Conti blender

• High levels of intermixing reduces feeder variance• Use RTD to determine if the variance in the feeders is removed

by intermixing in the blender• MBB

• No intermixing between MBB but feeder control is much more precise• AND we can set the granule weight as a ‘master’ and adjust the

extra-granulate and lubricant additions to always give the correct assay

• Blend uniformity (BU) within MBB is controlled by a DSp and BU between MBB = true BU

What about using the data for real-time release testing?

Justifying minimum data-set size for RTR

• When using data PAT data as part of RTR strategy, also need a strategy for missing data

• Bootstrap analysis to demonstrate that there is no appreciable difference in the attribute result calculated when 100% target sampling is achieved versus the minimum

Conclusions

• Control strategy isn’t about “control strategy”, it is about strategy to demonstrate you stay in a state of control

• In simplistic terms…..• In a batch-wise process we only have to demonstrate the process progresses as

expected and reaches the desired end result• In a CM processes we have to understand that we maintain a state of control

throughout the process• i.e. make decisions not just on individual steps but overall

• Control can mean simply determining ‘non-conformance’ and segregating• This is still a feed-forward control decision

• General we are trying to control within a DSp not to a specific product quality• Unless there is an approved DSp we cannot change recipe set-points outside there

acceptable range anyway

Thank you for your attention…..