Commonly Seen Drug Product Related Quality Deficiencies

Transcription

1 Commonly Seen Drug Product Related Quality Deficiencies 2016 GPhA CMC Workshop Bethesda, MD; May 18, 2016 Geoffrey Wu, PhD, CPH Lieutenant, US Public Health Service Associate Director for Science & Communication (acting) Office of Lifecycle Drug Products, OPQ, CDER 1

2 Outline Scope of discussion Major drug product related quality deficiencies Minor drug product related quality deficiencies 2

3 Scope of discussion Commonly seen quality issues related to the drug product aspect Focus on major and 3

4 major deficiencies Unqualified impurity levels due to toxicity The proposed limit for the impurity containing structural alerts for genotoxicity was based on the wrong MDD calculation The proposed residual solvent level (no adequate tox data found) was based on wrong PDE calculation. it is not appropriate to calculate PDE that concerns chronic exposure through extrapolation of acute toxicity data Properly determine the MDD Follow ICH M7 (e.g., NMT 1.5 mcg/day) Generate new tox data simulating the expected use (e.g., route of administration, chronic use) properly determine PDE 4

5 major deficiencies CQA failure or not identified/controlled Dose dumping not controlled Reformulation needed Actual droplet size 30-50% larger than the RLD s Pump metering reproducibility not acceptable Lack of monitoring and control over salt free base conversion Lack of control over the identified DS degradants Control droplet size within 10% of the RLD s and with similar variance Need tighter control over the weight of individual sprays Add such a critical attribute to the spec for release and stability Develop stability indicating analytical method(s) Add specs for all for release and stability 5

6 major deficiencies New packaging system/component is needed. Color of the product closure is not consistent with (the RLD s or) AAO color codes Type III DMF (packaging material) referenced was closed/inactive. A different supplier is needed. Change the color to comply an aspect critical to the patientproduct interface Identify and qualify another CCS Important to stay abreast with the DMF status* Always important to keep in touch with the DMF holder(s) (e.g., for API, critical excipients, and critical packaging components) AAO: American Academy of Opthalmology CCS: container closure system 6

7 major deficiencies Analytical method not stability indicating or suitable The proposed related substance analytical method is not adequate to resolve the artifact peak Lack of stability indicating assay method for the drug substance New method needed with adequate validation New method needed with adequate validation/verification 7

8 Unjustified drug substance overage or excess An overage of x% was proposed without justification X% of excess drug substance is proposed in the master batch record without justification Sufficient justification is needed, or remove the overage, or reduce to a certain level (e.g., referencing the RLD) Justification needed or refine manufacturing process to minimize drug substance loss In general, use of an overage of a drug substance to compensate for degradation during manufacturing or a product s shelf life, or to extend shelf life, is discouraged. (ICH Q8(R2)) Overage and overfill should distinguished and justified. 8

9 Drug substance polymorphism and chirality Missing control of the desired drug substance polymorphism Establish a spec and provide sufficient justification and validation of the method Missing a spec for optical rotation for the drug substance Establish a spec and justify accordingly to ensure the drug substance is a racemic mixture 9

10 Drug substance residual solvent Missing a spec for a residual solvent in the drug substance Establish a spec for the indicated solvent in the drug substance Consider potential impurities (e.g., benzene in ethanol) in residual solvents as needed. 10

11 Drug substance particle size Proposed particle size acceptance criterion (e.g., only D90) was not sufficiently justified. Lack of particle size distribution spec for the API Establish acceptance criteria for D10, D50 and D90* Establish one to ensure the uniformity of the drug substance in the resulting product (gels and ointment) Acceptance criteria can be established based on the particle size distribution of the drug substance used in the bio-batch. 11

12 Excipient Lack of microbial limits in drug product release Insufficient excipient compatibility study since the API may convert to free base under the influence of excipients and moisture Lack of particle size control/spec for critical excipients Establish microbial control for release and stability when most inactive ingredients are hygroscopic Evaluate the compatibility of the API and excipients with the presence of moisture Establish particle size control for critical excipients to ensure consistent drug product quality, in case of change of vendors. 12

13 Drug product CQA or attributes Assay limit for stability was too wide Tighten by comparison with the RLD close to expiry to ensure strength (especially for an NTI drugs) Missing a time limit for the reconstitution time Missing a spec for water content in the DP Missing a spec for the capsule brittleness in the stability specs NTI: narrow therapeutic index Add as part of the release and stability specifications Establish a spec for water content and justify accordingly Establish a spec to assure capsule integrity during shelf-life 13

14 Method validation Method needed to be revalidated due to insufficient forced degradation studies Did not use certain impurity standards during method verification upon transfer Validation did not cover the range needed Ideally 10-15% of degradation of the API is needed to sufficiently validate the proposed analytical method All impurity standards should be used to sufficiently verify the analytical method when transferring Method validation needs to cover the appropriate range (e.g., lower limit, LOQ) 14

15 Scored tablets Lack of testing of the split tablets Conduct recommended tests (e.g., weight variation, in-use stability, dissolution) on the split tablets per the Tablet Scoring guidance* *Guidance for Industry Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation (March 2013) 15

16 Stability protocol Outdated stability protocol due to changes to certain specifications Lack of justification for the selected time points in the stability program Certain pre-approval stability conditions (e.g., refrigerated) were not included in the post-approval stability program Stability protocol needs to be updated to reflect the up-to-date specifications Justify following the recommendations from ICH Q1D It is important to ensure the consistency in pre- and postapproval stability conditions 16

17 Questionable stability trends Trends (e.g., potency loss, dissolution slowing down after stored under accelerated conditions) shown during stability study without further investigation If trend is observed, root cause analysis should be conducted and corresponding risk mitigation plan should be devised. 17

18 Additional points to consider Product understanding failure modes risk mitigation Deficiencies = unattended failure modes Pharmaceutical equivalence: same drug substance(s), strength(s), route of administration, what else? patient interface (e.g., dosing device, tablet/capsule size, tablet splitability, and CCS color code) Submission quality is a reflection of the applicant s handling of the product and QMS Credit Trust 18

19 Acknowledgment OPQ: Susan Rosencrance Glen Smith Andre Raw Kristina Adams Fang Yuan Hardik Patel Xinming Liu GPhA: Lisa Tan Thank You! 19