Evolution of Quality Assessments Recent Trends in FDA Queries. Mike Saleh, Pfizer Inc.

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Thomasine Campbell
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1 Evolution of Quality Assessments Recent Trends in FDA Queries Mike Saleh, Pfizer Inc.

2 Outline 1. Background 2. Assessment of Information Requests from Recent NDAs 3. Distribution of queries (by focus area) Process Control Specifications Analytical Formulation Stability 4. Conclusions Where are we Aligned with Regulators Areas of Improvements Common Goals

3 Background - Evolution of Quality Assessment Office of Pharmaceutical Quality (OPQ) formally launched in January 2015 Foundation for systematic approach to product quality knowledge has evolved Industry saw the signals earlier Good signals Janet Woodcock s quote on moving from a rule-based to a Risk-based Approach Recent Pre-approval Inspections (PAI) Reviewer and inspector at site are working side-by-side with Industry Evidence is in the diversity of Information Requests (IR)received from the Agency in recent years

Distribution of Queries (Pfizer s NDA Submissions) Time frame = 2011-2015 6 Recent NDAs Varying degrees of QbD(With & without DS) New Products with Various Indications Solid Oral Dose Products

4 Distribution of Queries (Pfizer s NDA Submissions) Time frame = Recent NDAs Varying degrees of QbD(With & without DS) New Products with Various Indications Solid Oral Dose Products (Tablets + Capsules) Immediate Release + Modified Release Total queries = 193 5% 9% 16% 10% 28% 32% Process Control Specifications Analytical Stability Formulation Misc (Label+BP +CCS+EA) Top 5 areas = 90% of queries Natural overlap between the top 5 areas, e.g., Specs + Proc Ctrl --(QbD)

5 Process Control (1) Criticality Assessment In early QbD submissions, criticality assessment was not viewed to be in-line with ICH Q8, Q9, and Q10 A glaring gap between Industry & regulators Pfizer s Approach: 3-tier System: critical, non-critical, and key FDA/ICH: 2-tier System: critical, non-critical Painful beginnings, but remarkable progress achieved Design Space Pfizer conducts most DOE studies & multi-variante experiments at lab/pilot scales with justifications for PARs that are scale-independent (scale-up) FDA requests from firms to commit to verify all ranges at scale Industry and Agency are working towards better alignment with respect to verification of Design Space (DS) at scale End Result Proposed DS was ultimately agreed upon with some commitments FDA requests were not seen as requirements for approval

6 Process Control (2) Process Description Early on Process description was more focused on Critical Process Parameters (CPP), less emphasis on non-cpps Some Normal Operating Ranges (NOR) not included in Process Description (non-cpps) Insufficient details leading to provide batch records with full details Learning curve for Pfizer Level of details continue to be a negotiating point Great improvements continue thru dialog with Agency Recent submissions showed less queries related to this topic Change Control Pfizer s approach to handling changes to non-cpps(firm s quality systems) Dialog is still ongoing on handling these changes (PQS or AR) New FDA Draft Guidance on Established Conditions is a good step forward towards more clarity on reportable CMC changes

7 Process Control (3) Movement within DS - Stability FDA view Ensure that stability of product is independent of movement within the proposed design space Include in your post approval stability program plans to monitor stability of batches manufactured at commercially unverified areas of the design space Pfizer s view Risk assessment is conducted Impact would be first observed on release If change has a direct impact on stability, then we do place batches on stability Less benefits or regulatory relief is viewed by Pfizer /Industry when claiming design space

8 Specifications Issues Impurity Specs Pfizer base their specs on clinical relevancy and also on toxicology data FDA takes clinical/toxinfo into consideration, but appear to take the capability of the process into more consideration Example: In one of the products, Pdspecs were set at allowable PDE, but FDA asked us to reduce to lower value based on batch data In this case the material was very clean which helped us drive down the levels of Pdbased on batch data What is the Industry s expectations?? Compromise between capability of Process & tox data

9 Specifications Issues Particle size specs Pfizer s view: Use of modeling to predict drug substance particle size distribution is acceptable FDA s view: Batch data to support the appropriate acceptance criteria for DS particle size is very important Basis for setting specs Dissolution method Optimized dissolution conditions not clearly justified Solution Share your regulatory Disso method with Agency prior to NDA very beneficial for products with IVIVc (clinically-relevant specifications) Microbiological Testing for Solid Oral Dose Pfizer s Approach Careful consideration into: Microbial growth Water activity Up-stream processing Excipient Controls FDA expectation - Absence of testing must include very strong rationale, not just data from a few batches

10 Analytical Range of Issues dissolution, method validation, system suitability, and IPCs Alternating between 2 methods/analytical techniques, e.g., NIR/HPLC for Assay and ID, or UV/HPLC for dissolution AQbD - Use of statistical approaches to method validations is still at its early stages of understanding for both Industry and Regulators Lessons Learned - There is a potential for future regulatory dialog on this topic

11 Formulation Issues (BE-related) Interesting case of a Product where the design space of excipients is very wide Sodium Starch Glycolate range = 1% - 6% Magnesium Stearate Range = 2% - 3% In vitro data support levels of Sodium Starch Glycolate (4-5%) Magnesium Stearate (2-3%) FDA view of Design Space Variations of this magnitude are considered Level 3 changes according to SUPAC-IR Need to demonstrate how bioequivalence (in vivo data) is assured within the proposed ranges in these excipient levels in your design space (especially at extremes of DS) From bio-performance perspective this is where both Industry & Agency may be more aligned in terms of Risk assessment (based on in-vitro performance) to justify the need (or not) for in-vivo studies

12 Stability Annual Stability For Products with Multiple strengths and/or multiple presentations Pfizer utilizes science & product knowledge to select representative batches for annual stability program (same manufacturing process, common blend; place product with worst case MVTRas a representative) FDA view Annual stability to include one batch per year per strength per packaging configuration Lean Stability Approach Pfizer - adjust frequency of testing, eliminate non-stability indicating tests such as Assay Justification you can fail on stability by impurity well before you fail on assay and then assay becomes less of a stability indicating measure More alignment on stability indicating attributes may be needed Consult Agency prior to committing to Lean Stability Approach

13 Conclusions Consistent drug product quality assessments has been observed IRs equate to deficiencies in information provided in a submission, but do not necessarily reflect a deficiency in Firms development programs It is all about the clarity of information provided in the dossier and shared with Regulators

14 Where are we aligned with regulators? Criticality Assessments Rough beginnings, but great progress achieved This has been an evolution for every one Initial years were very painful, but over the past 2 years we revised and changed the ways we describe our processes in a concise manner acceptable by the Agency Better job of writing the story (esp. S.2.6& P.2.3) Process Description More details are provided (S.2.2& P.3.3) Control Strategy Description Links between input parameters & product quality attributes also evolved

15 Areas of Improvements with regulators Confusion regarding which elements of an application are considered to be binding, or commitment sections New FDA Draft Guidance on established conditions represents a major step towards more alignment Sometimes, we are faced with a clashbetween science & regulations; Challenge is in how to balance between Science and regulations and to ensure that quality in products is maintained

16 Common Goals for Industry & Regulators We are approaching the Desired State Field inspector next to reviewer at site inspections Robust Manufacturing Robust Quality Products Less Recalls/Less Defects Less Post approval supplements Win/Win for All

How to Identify Critical Quality Attributes and Critical Process Parameters

How to Identify Critical Quality Attributes and Critical Process Parameters Jennifer Maguire, Ph.D. Daniel Peng, Ph.D. Office of Process and Facility (OPF) OPQ/CDER/FDA FDA/PQRI 2 nd Conference North Bethesda,