Control strategy and validation. Emanuela Lacana PhD Office of Biotechnology Products CDER/FDA

Transcription

1 Control strategy and validation Emanuela Lacana PhD Office of Biotechnology Products CDER/FDA 1

2 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 2

3 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 3

4 Q6B (1999) ICH Early Mentions 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. Adapted from Moheb Nasr and Steve Kozlowski 4

5 ICH Early Mentions, cont. 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 5

6 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

7 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

8 ICH Q11 Example 5a. Possible Control Strategy Summary Biotechnological Products Drug Substance CQA Contaminant (Viral Safety) Control Strategy for drug substance CQA Summaries of viral safety information for biologically-sourced materials Detailed information including for materials of biological origin, testing at appropriate stages of production and viral clearance studies Section(s) in CTD where detailed information is located 3.2.S A.2 Residual Host Cell Proteins Specific Glycoforms Design Space for an individual unit operation (e.g. see Example 3) Target range for consistent removal assured by validation Analytical procedures and their validation 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.) Characterisation to justify classification as CQA (cross reference to nonclinical/clinical sections if relevant) Control of Critical Steps, Testing program and specifications Justification of specification Stability 3.2.S S S.4.2, 3.2.S S S S.2.4, 3.2.S S S.7

9 Control strategy in summary Planned set of controls Process design and development Specifications Monitoring That assures process performance and product quality Raw Materials Facilities and equipment Control Strategy In-process controls Parameters and attributes Desired Product 9

10 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

11 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 11

12 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 12

13 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 13

14 Continued Process Verification What s new? Formalizes expectations for a state of control Information gathering and review process is dynamic and data-driven 14

15 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.. 15

16 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 16

17 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 17

18 Element of a control strategy, cont. Cross-site evaluation of product to avoid drift Risk assessment and management Robust PQS Clinically relevant specifications 18

19 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 19

20 Regulatory Reporting Mechanisms 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

21 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 changes 21

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23 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 strategy submitted in the application may be considered established conditions 23

24 Overall control strategy Described to support product and process Managed by PQS Reportable Post approval 24

25 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.

26 Examples of established conditions, cont Specifications Analytical procedures Reference standards or materials Container closure system Protocols Drug product specific Excipient, batch formula, composition 26

27 Generally not established conditions Batch records Development data Characterization Validation data Batch analysis data 27

28 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 28

29 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

30 Questions? 30