Control strategy and validation

Emanuela LacanaPhD

Office of Biotechnology ProductsCDER/FDA

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Disclaimer

The views and opinions expressed in this presentation are those of the speaker and should not be used in place of regulations,

published FDA guidances or discussions with the Agency

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The history of control strategy• Defined in several ICH guidances

• Evolved over a period of time

• Reproducibly provide high quality, safe and efficacious medicinal products– A shared goal of FDA and industry

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ICH Early Mentions• Q6B (1999)

– Specifications are one element of a total control strategy

– Other elements include:• product characterization• adherence to cGMPs• a validated manufacturing process• raw materials, in-process & stability testing, etc.

4Adapted from Moheb Nasr and Steve Kozlowski

• Q8 (2006) and Q10(2008)– At minimum, pharmaceutical development

section should include the definition of control strategy [and justification]

– Using enhanced product and process understanding in combination with quality risk management to establish an appropriate control strategy

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ICH Early Mentions, cont.

Q8 and Q10 definition of Control Strategy

– 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 • facility and equipment operating conditions,• in-process controls,• finished product specifications,• associated methods and frequency of monitoring and

control 6

ICH Q11 Drug Substance (2012)• A control strategy can include, but is not

limited to:– Controls on drug substance (e.g., release testing)– Controls on material attributes (including raw

materials…)– In-process controls (including in-process tests and

process parameters)– Controls implicit in the design of the

manufacturing process (e.g., sequence of purification steps…) 7

ICH Q11 Example 5a. Possible Control Strategy Summary – Biotechnological Products

Drug Substance CQA

Control Strategy for drug substance CQASection(s) in CTD where

detailed information is located

Contaminant(Viral Safety)

Summaries of viral safety information for biologically-sourced materials 3.2.S.2.3Detailed information including for materials of biological origin, testing at

appropriate stages of production and viral clearance studies3.2.A.2

Residual Host Cell Proteins

Design Space for an individual unit operation (e.g. see Example 3) 3.2.S.2.2Target range for consistent removal assured by validation 3.2.S.2.5Analytical procedures and their validation 3.2.S.4.2 , 3.2.S.4.3

Specific Glycoforms

Controls implicit in the design of the manufacturing process including a summary of process control steps (e.g. cell culture conditions, downstream purification, holding conditions etc.)

3.2.S.2.2

Characterisation to justify classification as CQA (cross reference to non-clinical/clinical sections if relevant)

3.2.S.3.1

Control of Critical Steps, Testing program and specifications 3.2.S.2.4, 3.2.S.4.1Justification of specification 3.2.S.4.5Stability 3.2.S.7

Control strategy in summary

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Control Strategy

In-process controls

DesiredProduct

Planned set of controls That assures process performance and product quality

Facilities and equipment

Raw Materials

Process design and development

SpecificationsMonitoring

Parameters and attributes

Control strategy is built upon

• Understanding of product and process– Adequate process development and product

characterization• “Know thy product”: quality attributes, how they may be

linked to process• “Know thy process”: understand and control those variables

that impact process performance and product quality

• Validation of the process– Exercise that scientifically establish that a process is

capable of consistently delivering a product that meets the expected quality criteria

– It is a state, not an event 10

Continued Process Verification• Assure that the process is continually in a state

of control– Monitoring and sampling, adjusted as needed based

on data collected • Systems capable of detecting unplanned variations

– Evaluate sources of variability to control and reduce variation

• Common cause variability• Special cause variability

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Continued Process Verification• Need an adequate program to collect and

analyze process data– Trending in-process data– Evaluation of in-process materials– Evaluation of products

• Statistical trending of data– Product related data– Statistical process control

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Continued Process Verification• Facilitate process optimization and

improvement– May identify areas of improvement in the

process• Changes needed to maintain product quality• Need for additional process design and

qualification to optimize the process

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Continued Process Verification• What’s new?

– Formalizes expectations for a “state of control”

– Information gathering and review process is dynamic and data-driven

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Examples of what is not CPV• A substitute for inadequate process

development– PAI during an original BLA review cycle

– Process changes made on almost daily basis to adjust and tweak multiple unit operations

– As a result, the actual process was quite different from the process submitted in the BLA to support the license

– Justification: It is in the spirit of what FDA described in the PV guidance…..

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Examples of what is not CPV• Changes proposed without keeping the

product in the line of sight– Change in a piece of equipment resulted in

increase in oxidation and loss of potency– Proposed changes in specifications to “fit” the

current results– Would result in changes in product quality

beyond clinical experience

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Element of a control strategy• Adequate control on raw materials

• Well designed manufacturing process– Appropriate in-process controls – Critical and key parameters– Appropriate alert and action limits– Statistical process control– Appropriately qualified equipment

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Element of a control strategy, cont.

• Cross-site evaluation of product to avoid drift

• Risk assessment and management

• Robust PQS

• Clinically relevant specifications

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Changes to an approved application

• Result from knowledge acquired post-approval (CPV activities)

• Process, product, facilities

• Managed and executed in conformance with cGMP

• Reported to the Agency per appropriate regulation

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Regulatory Reporting Mechanisms601.12 An applicant must inform the FDA about each change in the…[conditions] established in the approved license application(s).

• PAS-- substantial potential to have an adverse effect on the… product… safety or effectiveness

• CBE 30-- moderate potential [of] an adverse effect• In certain circumstances… may be distributed

immediately upon receipt…

• AR-- minimal potential to have an adverse effect• Protocols to reduce reporting categories

What changes are reported?• Is everything in the BLA a commitment?

• Uncertainty on what is a commitment leads to:

– “If we do not submit that we will not need to report a change”

– “My QA person told me that if I submit this SOP I will need to submit a supplement every time I make a change”

• Need for clarity on reportable changes21

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Established conditions• Description of the product, manufacturing process, facilities and

equipment, and elements of the associated control strategy, as defined in an application, that assure process performance and quality of an approved product.

• Not all that is submitted in an application is an established condition

• The guidance clarifies which elements of the control strategysubmitted in the application may be considered established conditions

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Overall control strategy

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Managed by PQSDescribed to support product and process

ReportablePost approval

Examples of established conditions

• Drug substance and product manufacturing processes:– Manufacturing and testing facilities – Description of manufacturing process– Source and specifications for biologics starting materials – Process, including in-process tests and sequence of operations,

equipment; and process parameters.

• Specifications, including tests, procedures and criteria• Container closure system, components, and specs.

• Specifications– Analytical procedures– Reference standards or materials

• Container closure system• Protocols• Drug product specific

– Excipient, batch formula, composition

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Examples of established conditions, cont

Generally not established conditions

• Batch records

• Development data

• Characterization

• Validation data

• Batch analysis data

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Process• Submitted by the Applicant (recommended

in module 2)

• Evaluated by the Agency– Product and process understanding– Risk assessment and mitigation strategies

• Finalized after negotiation at the time of licensure

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Benefits of clearly defined established conditions

• Reduce submission of unnecessary supplements– Effective post approval submission strategies

• Encourages continual process improvements

• Allows FDA to better regulate post approval changes– more flexibility– Risk based principles 29

Questions?

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