26 MAY 2016 Line Lundsberg-Nielsen, Vibeke Brun Jensen & Monica Hueg. Implementing CPV in Smaller Organizations

Transcription

1 26 MAY 2016 Line Lundsberg-Nielsen, Vibeke Brun Jensen & Monica Hueg Implementing CPV in Smaller Organizations

2 Outline CPV/OPV regulatory expectations, differences and similarities Challenges for smaller non-us companies CPV/OPV Roadmap Case study: OSD product 2

3 CPV/OPV expectations Are there actually any real differences in expectations? Both FDA and EMA refer to a three stage life cycle approach to Process Validation that is science and risk based and supported by ICH Q8, Q9, Q10 and Q11 The FDA has, since 2011, required that CPV programmes should be emplaced for both new and legacy products With Annex 15 coming into force Oct 2015, EMA also expect that OPV programmes for new and legacy products will be emplaced So what is the problem in Europe? If there even is a problem? Why is it so complex and difficult to implement CPV/OPV? 3

4 PATIENT & Product Focus Science & Risk Based Approach EMA FDA Lifecycle Approach to Process Validation - FDA and EMA Development Technology Transfer The Product Life Cycle Commercial Manufacturing Product Discontinuation During Development Before Sales During Commercial Manufacturing Process Design Stage 1 ICH Q8, Q11 (Inspection) Pharmaceutical Development ICH Q8, Q11 Dossier (Submission) Process Qualification Stage 2 (Inspection) Facility, Utility & Equipment Qualification Stage 2.1 Process Performance Qualification Stage 2.2 Qualification (Equipment) Annex 15 Process Validation (PV Guide, Annex 15) Traditional, Continuous Process Verification (PAT) or Hybrid (Submission, assessment, GMP, Inspection) Continued Process Verification Stage 3 (GMP, Inspection) ICH Q10 Link to Annual Product Review Quality Risk Management (ICH Q9) & Pharmaceutical Quality System (ICH Q10) Ongoing Process Verification Annex 15 (GMP, Inspection) ICH Q10 Link to Product Quality Review 4

5 FDA versus EMA expectations to CPV/OPV Ref.: Grace McNally, FDA, CDER, OPQ, OPF, FDA PDA Joint Reg Conf; Washington D.C., Sept

6 The Challenges (maybe not only in Europe.) Concepts and skills Lack of lifecycle process validation concept Lack of the needed skill sets or in house training e.g. statistical skills Do not know how to start the implementation of CPV/OPV (particularly difficult for legacy products) Products not prioritized in terms of patient, quality and supply risk. Procedures Lack of procedures or templates for the three PV stages Lack of procedures for how to apply statistical tools in PV and how to act on the outcome of the analysis Lack of procedures for data collections from manual processes Unclear nomenclature Process Understanding Minimal process understanding No overview of the real product and process risk Lack of QTPP, CQAs or CPPs Investigate process variation to and understand sources, to control them Quality Risk Management (QRM) Lack of QRM procedures in place and if, they are not operational (typically just copies of the standards and guidelines) Very few useful risk assessments If they do risk analysis, it is often very complex with lack of overview and done as a one off activity 6

7 More Challenges ( and still not only in Europe.) Regulatory Expectations Limited knowledge of the differences and similarities between the FDA and EMA expectations on PV How to comply with them both? APR/PQR We do PQR (APR) so why OPV (CPV)? Pharmaceutical Quality System (PQS) Reluctant to move to the new lifecycle PV paradigm and change PQS accordingly See the new OPV/CPV expectations as additional elements to their existing Quality System. Patchwork when new PV elements are added. Becomes very complicated requires lot of work with limited value Attitude They will have to change their mind-set 7

8 Intelligence is static Leads to a desire to look smart Avoid challenges Get defensive or give up easily See effort as fruitless or worse Ignore constructive (negative) feedback Feel threatened by the success of others Result: they may plateau early and fail to reach their full potential Fixed Mindset vs. Growth Mindset Fixed Mindset Growth Mindset Intelligence can be developed Leads to a desire to learn Embrace challenges Persist in the face of obstacles See effort as the path to mastery Learn from criticism Find lessons and inspiration in the success of others Result: they reach even higher levels of achievement Based on The Mindsets : C. Dweck, Professor of Psychology, Stanford University 8

9 So what do we use a new Growth Mindset for? Process Validation Lifecycle Stage 2: PPQ/PV Stage 3A: CPV/OPV Stage 3B: CPV/OPV Is the commercial process capable of producing reproducible products? We must demonstrate being In Control Capable Reproducible Does the process remain in a state of control? What is the Performance? We must ensure the process is: Predictable Capable Does the process remain in a state of control? Predictable, Capable, Performance Ongoing detection of Process and Product Variability and Drift 9

10 Establishing a CPV/OPV Programme The basis for making a CVP/OPV Programme depends on whether the CVP/OPV is to be performed for a new product/process or an existing product/process For a new product the CVP/OPV is based on knowledge obtained during Process Design and PPQ/PV For legacy products where CVP/OPV will be established for the first time, the CVP/OPV will be based on prior knowledge from the years of commercial manufacturing including the initial PV prior to product launch 10

11 CVP/OPV for legacy products where do you start? A good starting point for establishing a CVP/OPV programme for legacy products and thereby complying, is to evaluate the products by prioritising according to the risk to the patient, quality and supply Based on that priority list, the CVP/OPV programme for each product can now start to be built using a CPV/OPV roadmap 11

12 CPV/OPV Roadmap new and legacy products 12

13 Case study CPV/OPV for Product N A legacy wet granulated OSD product in two strengths, 10 and 20 mg tablets Around 50 batches manufactured per year with none or limited release problems Product assumed to be robust, no risk analysis has been performed The QTPP does not exists, CQAs and CPPs have not been identified Batch release data available for release attributes, including: Assay CU Dissolution Process performance and capabilities have not been calculated THE GOAL is to establish a CPV/OPV PROGRAMME and demonstrate the product remains in a state of control by monitoring relevant product and process data and, by evaluating the Cpk and Ppk 13 IFPAC Jan 2016 Implementing CPV Lundsberg & Hueg, NNE Pharmaplan

14 Prior knowledge current control strategy The existing control strategy is based on end product testing, IPCs and raw material testing: 14

15 Initial product quality and performance baseline Assay A statistical evaluation of the performance and capability of the release attributes and the IPCs were performed for the last 50 batches Assay No special cause variation observed The process is shifted by nearly 1% in assay but is stable and well within the specifications No additional monitoring activities are required Analysis of the Assay 15

16 Initial product quality and performance baseline Dissolution Dissolution Dissolution is within specification but the variation could lead to a dissolution value below target The root cause of this variation must be explored and action taken to improve Analysis of the Dissolution 16

17 Initial product quality and performance baseline Granule particle size Granule particle size The particle size varies significantly The process is not in control OOSs are observed The impact of this variability on the product quality must be understood Further investigation to find the root cause of this variability must be made Analysis of IPC granule particle size 17

18 Initial baseline for Product N Analysis summary See table A Cpk and Ppk of more than 1.6 is classified as the process being robust (green), between 1 and 1.6 being average (yellow) and below 1 weak and non-robust (red) The CPV/OPV Programme will focus on what is critical (red) 18

19 The CPV/OPV Programme (I) 19

20 The CPV/OPV Programme (II) 20

21 CVP/OPV Report The outcome of the CPV/OPV activities must be documented in an CPV/OPV report The report will cover the data presentation, plots and analysis Conclusions based on the analysis in terms of: Root cause analysis Improvement activities Change to the control strategy Changes to the CPV/OPV programme Analysis of IPC granule particle size Batch

22 CPV/OPV Report, granule particle size The variability of the granulate particle size shows an insufficient robustness of the granulation process A correlation between the granulation fluid spray rate and the granulate particle size could not be demonstrated The root cause for variations in the granulate particle size needs to be further evaluated It has been proposed that other process parameters must be monitored during granulation, such as air flow rate. As well as additional sampling during granulation process to increase process understanding 22

23 CVP/OPV Report, assay Analysis of Assay Batch Based on the evaluation of the 50 batches and the acknowledging the process is very robust, the control limits have been defined to: LCL: 98.9 % label claim and UCL: % label claim These control limits will be used for the ongoing monitoring programme used as basis for levels and frequency of routine sampling and monitoring 23

24 Lifecycle CPV/OPV Approach The initial risk assessment can now be updated The CPV/OPV Programme must be updated if any changes are proposed in the report in relation to: The Control Strategy Monitoring programme Monitoring Frequency Review Frequency As with the case of granule particle size, knowledge about critical steps and potential CPPs will evolve during the CPV/OPV 24 IFPAC Jan 2016 Implementing CPV Lundsberg & Hueg, NNE Pharmaplan

25 Conclusion Establishing a CPV/OPV programme requires a change in mindset and acknowledgment of the growth potential in process robustness and product quality the PQR/APQR is a status report and does not provide the same growth opportunities All the elements (data, information, knowledge) needed to set up a CPV/OPV programme are present (GMP data) it is just a matter of combining them in the right order to get the puzzle to fit. 25

26 Thank you for your attention and remember Line Lundsberg-Nielsen Vibeke Brun Jensen Monica Hueg 26