How a line-of-sight approach to shipping validation discovers both external and internal quality improvement opportunities

Transcription

1 How a line-of-sight approach to shipping validation discovers both external and internal quality improvement opportunities Chris M Hanff, CMQ/OE Senior Consultant and Project Lead CONCORDIAValSource, LLC

2 How a line-of-sight approach to shipping validation discovers both external and internal quality improvement opportunities

3 Purpose & Aim Purpose of this presentation: To present the importance and value of the shipping and its validation as a vehicle to improve the health of the entire QMS Aim Product:Patient Line-of-Sight focused on the points where active transport qualification intersect the Quality Management System

4 Outline Statement of the Problem/ Opportunity What should be in focus? Shipping illustration Line-of-Sight focus to QMS improvement SQM CoQ Validation Mfg. Controls Parting Thoughts

5 Statement of the Problem/ Opportunity Statement Problem Statement: Shipping and its validation get overlooked, which ignores risk and uncertainty in the supply chain Opportunity Statement: Vigilance about the shipping process raises improvement opportunities throughout the QMS

6 Is Shipping Out of Sight? Why? Amazon.com shipping is highly successful, fast, RELIABLE A box is a box is a box, right? Out of sight = out of mind We re ignorant of the process UNHERALDED work dock-to-dock Dark, dusty, hot/ cold, and UGGH it s unglamorous

7 Bulk Formulation CMO(s) Shipping is Elaborate Handling (Procedural) Controls Distributor(s) Wholesaler(s)? Personnel Controls Warehousing Engineering Controls Shipper(s)

8 Shipping is Elaborate Bulk Formulation Quality Assurance CMO(s) Mfg. Controls Distributor(s) SQM Wholesaler(s)? Warehousing Validation Shipper(s) CoQ

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10 Line-Of-Sight

11 Transport Equip DQ, I/O-Q? Equipment DIS/Qualified List Break-Loose & Glide Force Line-Of-Sight Quality Agreements Quality Oversight (+ +++) Data Management FMEA feedback to Dev. Mfg. Controls 3PM and RACI Cost of Quality Knowledge Management

12 Line-Of-Sight Two-Part Approach 1. See a need, fill a need Look for what works and what doesn t work Be courageous, courteous, & challenge status quo

13 Line-Of-Sight Two-Part Approach 1. See a need, fill a need 2. Begin and continue with the End in mind Identify QTPP, CQAs, design space (= Stage 1 PV) Show process reliability, repeatability, keeping focus on end product CQAs (= Stage 2a, 2b PV) Keep vigilant that process stays in validated state (= Stage 3a, 3b PV)

14 What s Missing? What s in Focus RE:Shipping? Exceptions Mgmt., RACI, Q.Ags.,... QMS Integration Shipping Routes Shipping Costs Packaging Design Time & Temperature

15 What s in Focus RE:Shipping? Packaging (re-re-re-re)design 1º package (product contact container) gets its due attention, right? 2º package (carton) may be overdeveloped* Should it matter to the patient what carton holds the medicine? 1-count, 2-, 4-, 5-count? How could it? Just count how many carton revisions are made, even from one product to another in the same product family

16 Line-Of-Sight Focus at Shipping Why call out 2º package/carton? Nothing else matters than right here Line-of-Sight focuses through commercialization to the patient... and, shows what s value added Line-Of-Sight?

17 What s in Focus RE:Shipping? Packaging (re-re-re-re)design Can you connect a line from patient to carton? CQAs anchored at patient: drug product (SQIPS); primary package to protect drug product secondary package to minimize physical stress CPPs tether manufacturing process to CQAs Curb carton designs not value added: Limit resource spend on carton to satisfy labeling compliance and safeguard integrity of 1º package

18 L-O-S:QMS Connection Consider QUALITY COSTS (CoQ) at Packaging Give Marketing and Packaging Engineers a budget Allocate and measure spending by quality costs: Scrap; Appraisal; Preventive Think with the end in mind and make carton revision decisions informed about the quality costs in comparison to the product:patient requirements Establish quality costs during validation to be continued in commercialization Remember L-O-S

19 L-O-S:QMS Connection Theory of Constraints adaptation Product Transport constraints: standard pallet sizes standard sizes for a ULD standard quantity cold-charge (dry ice, refrigerant) these dimensions define an element of the packaging design space and it s not really changed since 1931 so, why are we re-inventing the wheel? Find the appropriate balance to maximize units shipped successfully and minimize costs (as above, and not just the bill you pay FedEx or UPS)

20 What s in Focus RE:Shipping? Shipping Risk Assessments in Focus Shipping & Distribution reliance upon third-party LSP and CMO firms; and, Knowledge Transfer (KM) is weak Too often, no quality oversight/ connection

21 Shipping Process & Q. Oversight FMEA exercise relies on process controls: Engineering: ULDs, Reefers, Vehicles, Dataloggers Procedural: Cleaning/ turnover, deviation mgmt. Personnel: Staff qualifications, licenses Process is a composite of above controls Many above controls at 3PO (3 rd Party Orgs.)

22 Shipping Process & Q. Oversight FMEA Quality Oversight Guidance for Industry - Contract Mfg. Arrangements for Drugs: Quality Agreements the Agency considers contractors an extension of the manufacturer s own facility. ICH Q7 Good Manufacturing Practice Guidance for [APIs] recommends that manufacturers evaluate contractors for CGMP compliance both by establishing a formal agreement that delineates CGMP responsibilities

23 Shipping Process & Q. Oversight Quality Agreements w/ LSPs: Quality agreements and quality audits with shipping partners can provide validation information leverage into the shipping validation strategy Work carried out and documented at shipping partners can be assured, without need to repeat or duplicate the same testing by license holder

24 Shipping Process & Q. Oversight Why no Q.Ags with LSPs? but we have a complicated arrangement Set alignment on shipping validation strategy and project work with 2 techniques: Document Based Planning RACI Matrix

25 Shipping Val n. Doc.-Based Planning Through ordered compilation and communication of roles and responsibilities, Document-based Planning can identify all end state shipping validation deliverables Documented product validation coverage Documented shipping route & chain of custody (Shipping Maps) Roles & Responsibilities made clear (RACI & Q.Ags.) Validated span of shipping parameters; Known products coverage in validated spans Expectations (i.e., design specs ) in SVP, Quality Agreements, & Audits Documented Shipping Route (Map) Documented Shipping Partners

26 Shipping Val n. Doc.-Based Planning Site Level: SV Plan Purpose & Approach SV Plan Appendixes (existing) Products (new) Controls & Equipment SV Program: 3 rd Parties & Controls Audits, Q.Ags. RACI* Risk-based White Paper(s) SV Equipment Index: Validated, Verified In Use, Val n Status Ex Use, Val n Status Dis-Qualified Product Specific: Product Families (X, Y, Z) Products (A,B,C) Shipping Route Maps Shipping Process FMEAs

27 Shipping Process & Q. Oversight R.A.C.I. 1 Terms Responsible does the work to complete an activity or task Accountable has ultimately ownership for the correct completion of the activity or task; approval Consulted judgment sought about the completion of the task, performed by R Informed is kept up to date about the progress of a task and/ or its completion; informed by R 1 ISPE Good Practice Guide: Project Management for the Pharmaceutical Industry

28 Shipping Process & Q. Oversight Responsible Accountable Consulted Informed Companies X,Y,Z [M.A.H.] X e.g., [C.M.O.] Y [L.S.P.] Z R A C I Task 1 X,Y X,Z Deliverable 2 X X Expectation 3 Y X X,Z Regulatory 4 Z Z Dossier 5 X RACI Matrix Answers questions: who notifies changes or events; who carries out the work; and who approves

29 Shipping Process & Q. Oversight Duty [C.M.O.] Suppliers [M.A.H.] Filler Service Providers Material Suppliers Contract Grantor License Holder Gain/ Maintain Market Authorization C I, N/A A Evaluate & Execute Need(s) for Supply Chain Oversight: Service Level Agreement (SLA) Quality Agreement (QAg) Quality Audit Perform operations in compliance with relevant CGMPs Resolve Field Customer Complaints Qualify Shipping Vehicles/ Systems: ULD Qualification, if airflight TC Truck Qualification, if road transit Box shipper Qualification, if sample transport A (CMO:Supplier) R A (MAH:CMO) R R A R, C as determined C as determined R R A A

30 What s in Focus RE:Shipping? Shipping Risk Assessments in Focus 2 nd take-away from Shipping Process FMEA Knowledge Transfer (KM) is weak Still often, no quality oversight/ connection

31 Shipping Process FMEA & KM RPN Distribution and Evaluation, Initial (left) and Final (below)

32 Shipping Process FMEA & KM

33 Shipping Process FMEA & KM What is the effect of in-flight pressure changes on the container closure integrity of syringes finished with needles and stoppers? KNOWNS UNKNOWNS Determination 4mm air bubble height at filling Air bubble volume at filling Calculated (127µL) Syringe dimensions Air bubble volume in flight Calculated (NMT 167µL) Pressure at time of fill Stopper movement Calculated Theo.Max. Pressure in flight Volume expelled Calculated Theo.Max. 1.3mm Maximum Theoretical stopper displacement within sterile envelope of at least 3.3mm 40µL Maximum Theoretical volume expelled within Volume in Container overage

34 Shipping Process FMEA & KM Max stopper travel assumes zero break loose force (i.e., zero friction at stopper, which is unrealistic yet conservative) All pressure-volume calculations assume constant temperature, which is controlled at 5 C +/- 3 C Assumes manufacturing control at NMT 4mm (height) gas headspace (4mm tall air bubble) Assumes air flight artificial environment NLT 11.2PSIA (pressure data available)

35 Shipping Process FMEA & KM Boyle s Law, PP 1 VV 1 = PP 2 VV 2 Solving for Volume at time of filling pressure (VV 1 ) Known: 4mm air bubble height in a 6.35mm diameter syringe (per schematics) VV 1 = ππrr 2 h, VV 1 = ππ * ( cm) 2 * (0.4cm) 2 VV 1 = 0.127cccc Solving for Volume at flight pressure (VV 2 ): PP 1 VV 1 = PP 2 VV 2 (14.7PSIA) * (0.127cc) = 11.2PPPPPPPP * VV PSIA 0.127cc = VV 11.2PSIA cccc = VV 2 = 0.167mmmm = 167µLL

36 Shipping Process FMEA & KM Boyle s Law, PP 1 VV 1 = PP 2 VV 2 Solving for air bubble height in flight (i.e., stopper travel toward flange) VV 1 = ππrr 2 h h = VV 2 ππrr cccc h = ππ( cm) 2 h = 0.527cccc

37 Shipping Process FMEA & KM Physics-based Conclusions Max. Theoretical stopper displacement = 1.3mm travel toward syringe flange OR Max. Theoretical liquid displacement = 40 microliters expelled out of needle e.g, PROD123 Fill volume spec: NLT 1.14mL. In process Mfg. control: NLT 1.25mL fill Air bubble (gas headspace): In process Mfg. control: NMT 4mm (meniscus : stopper face) Air bubble volume = NMT ml (cubic centimeters)

38 Shipping Process FMEA & KM So, what s the problem in the example? We created knowledge, right? at least, created information, but in a silo Stopper Travel, Mfg. Controls not linked (same for Break Loose Glide Force) Layers of Project Management teams inhibit access to data, disrupt contextual discussions (to grow data into info); and, obstruct knowledge transfer

39 Parting Thoughts When is your product more at risk than when it s out of your hands (control)? What will you do about it?

40 Line-of-Sight Summary CQAs CPPs CQAs Development Manufacture Supply Drug Administered Stage1-Design; Stage2a2b-PPQ; Stage3a3b-CPV Targeted Embedded Delivered Visualize the connection from product CQAs through PPQ to Development Ensure the work is in line with the vision: delivering a safe and effective product to the patient