Quality Approach to Drug cGMP – An Integrated re VIEW

1. Quality Approach to Drug cGMP – An IntegratedreVIEW Binh T. Nguyen, Pharm.D./M.S. Reg Sci GDUFA Supervisory Consumer Safety Officer CDR / USPHS Los Angeles Office District May 2014

2. Objectives • Describe FDA inspectional approach of drug manufacturers by quality systems • Provide examples of cases associated with drug quality systems • Emphasize quality and safety designed or built into process/product Disclaimer: This is the author’s opinion and does not represent Agency’s view

3. The Life Cycle of DrugsDo clinicians & patients think about high quality manufacturing when they administer drugs? Drug Mfg & FDA

4. Drug Administration Safety and Efficacy Do side effects come from the drug product and/or manufacturing practice? Drug Diluent (IVPB) and Drug Active Mixing Exercise What are some issues you may see with this mixing?

5. Potential Problems of Admixture • Did not make in ISO 5 • Did not wipe vial/IVPB with sterile alcohol before removing and transferring • Did not protect product from light • Did not put on “use by date” • Gowning deficiencies

6. The Law and Regulation • FD&C Act • 21 CFR 211/212 • Compliance Program 7356.002, Drug Manufacturing Process Inspection covering six systems: • Quality – Production • Laboratory – Facility/Equipment • Materials – Packaging/Labeling

7. The Gold Standard ManufacturingIs high quality built into the process/product? SAFETY and EFFICACY

8. Packaging/Labeling - Drug Quality Reporting System (DQRS) • Quantity missing: Pt seals pack & missing 2 active tablets. Pack not broken open. Can see sealed from mfg that way. She says 2 packs came that way. She went ahead & used one pack & the 2nd pack she noticed & contacted pharmacy. • Excess fill contents/volume: Opened sealed bottle of Drug XYZ from Company ABC and it contained 101 instead of 100 tablets.

9. P/L System – Packaging (483 items)21 CFR 211.192

10. P/L System – Packaging (483 items)21 CFR 211.63

11. P/L System – LabelingHydrocortisone 10mg/1ml, Pramoxine HCl 10mg/1mL, Chloroxylenol 1mg/1mL(Is this an approved drug?) • Is the product listed in OTC Drug Monograph? • Is the product listed in medical references (i.e. Lexicomp, Micromedex, Physician Drug Reference) • Is the product listed in the Orange Book?

12. P/L System – Labeling (Lexicomp Search)

13. Package Insert

14. P/L - Package Insert

15. P/L – Package Insert

16. P/L System – LabelingThe Red/Orange Book Search

17. Legal Status of Drugs • To be legally marketed, a drug must fall into one of the following categories: • The drug must be the subject of an approved application (NDA, ANDA) • The drug must comply with an OTC Monograph 21 CFR Parts 300-499 • The drug qualifies for “Grandfather” status 21 CFR Part 314.200(e) • DESI = Drug Efficacy Study Implementation

18. P/L System – Labeling

19. P/L System – Labeling 483 item21 CFR 211.137(b) • Drug product expiration dates are not related to the storage conditions stated on the labeling, as determined by stability studies. • Specifically, all ABC 10mg, 20mg, and 40mg drug products packaged and labeled in 60 and 1000 tablets bottles did not have stability studies to support their storage conditions "Store between 5o-30oC (41o-86oF)." All ABC drug products are currently assigned with 3 year expiration dating.

20. P/L - Compounding

21. Stability of Admixture "Solutions of norepinephrine 64 mg/L in NS or D5W can be stored in PVC bags at 4°C for up to 61 days with protection from light. This expiry date allows for up to 24 h storage at 23°C. Solutions that are not protected from light will retain only 90% of the initial concentration after storage for 39 days at 4°C. This storage period could include up to 24 h at room temperature, without protection from light." http://www.ncbi.nlm.nih.gov/pubmed/22478966

22. STABILITY DATA Chromatograms obtained during the 61-day stability study. A: Solution of norepinephrine 64.5 mg/L in 5% dextrose in water (D5W) on study day 0. B: Solution of norepinephrine 64.5 mg/L in D5W after 61 days of storage at 23°C, protected from light, with undetectable loss. C: Solution of norepinephrine 64.5 mg/L in D5W after 61 days of storage at 23°C with no protection from light; 93% of the original concentration remains. D = degradation products (see arrows). These degradation products were identical in retention time with those observed in the accelerated degradation study (Figure 1). It was apparent that 5-hydroxy methyl furfural, a degradation product of dextrose that was observed only in solutions prepared with D5W, increased over the course of the study and increased to a greater extent in solutions that were unprotected from light.

23. IntegratedreVIEW – P/L Q&A • Is there any drug product with grandfathered labels and labeling? • Are your products DESI (Drug Efficacy Study Implementation)? • Are drug references (i.e. Lexi Comp, AFHS, Micromedex) trust worthy for clinical use from an approval standpoint? • Who issues NDC numbers? Do they check for product validity (NDA / ANDA / OTC, etc.) before issuing NDC numbers? • Is “Rx only” on product label make it a drug? • What is the Pharmacology / Pharmacokinetic information required to be stated on the package insert (i.e. t1/2, distribution, bioavailability, excretion, etc…)?

24. Laboratory - ChemistryDQRS – Potency question • MD suspects potency issue with ABC product infusion bags based on unexpected _____ results. • This XYZ product generic ___ mg tablet i have been on for months until a few weeks ago instead of the pill being yellow it was white and i noticed it was not working at all for my pain and the yellow ones ALWAYS worked. I am on an increased dose from previous months and there is something seriously wrong with this medicine. They did more then just take out the yellow die. I pay ALOT of money to get relief of my pain monthly with transportation and dr. appt. and medicines, i pay over $300 a MONTH and i am in excruciating pain unless i take 3 or 4 of these. They are made incorrectly or something and something needs to be done asap.

25. Laboratory System - Chemistry • Common chemistry deficiencies • Lack of Audit Trail • Inadequate System Suitability Runs • Inadequate Method Validation/Transfer • Method is not stability indicating • Lack of equipment qualification • Lack of/inadequate OOS investigation • Lack of/inadequate impurity testing/method • Inadequate reference standard/qualification

26. Lab System – Chemistry (483’s) • 21 CFR 211.22(c) The quality control unit lacks responsibility to approve and reject all procedures or specifications impacting on the identity, strength, quality, and purity of drug products. Specifically, the Quality Assurance Unit fails to review and approve protocols, reports, and procedures impacting on the quality testing of drug products. For example, 1.QA allows the use of ICPMS's without having current equipment qualification 2.QA was not aware of chemists not following tuning check procedure 3.QA was not involved in executing protocol and report for NMR equipment qualification - equipment was used for drug testing prior to QA review and sign off 4.QA allows the use of GC's without having current equipment qualification 5.QA was not aware of chemists performing testing without method validation and/or method transfer 6.QA has no knowledge that electronic files from NMR, ICPMS, GC, and LC systems are delete-able 7.QA was not aware of multiple copies of the same worksheet can be printed 8.QA was did not always evaluate testing results (i.e. inadequate chromatography) before final results were reported to clients • 21 CFR 211.160(b) The following drug products were tested using non-stability indicating test methods which did not qualitatively and quantitatively monitor degradation products, process impurities, excipients, or other potential impurities. Many of the test method with forced degradation studies did not discuss the identification or testing for degradants which were found to be present during forced degradation studies while some other test methods did not have any forced degradation studies

27. Laboratory – MicrobiologyDQRS – Contamination • Contamination suspected: Had to go back to hospital ER after being administered ABC product. Flu like symptoms & some mental impairment. Also acquired a urinary tract infection due to the bacteria in the tainted ABC product. • Complaint: The customer reported seven incidents where the endoscopy patients experienced post-operation fevers and other flu-like symptoms (i.e. chills). According to the customer, patients experienced fevers ranging from 101oF – 104oF.

28. Laboratory System – Microbiology21 CFR 211.165(b) • Each batch of drug product required to be free of objectionable microorganisms is not tested through appropriate laboratory testing. Specifically, the firm's SOP … titled "Bacterial Endotoxin Test" is deficient in that: • There is no requirement for vortexing the finished product vial, ABC product, prior to sample preparation. • The firm did not follow USP <85> for Bacterial Endotoxin testing in checking pH by mixing a portion of the sample prep with lysate first before adjusting the pH of the sample prep solution. • There is no assurance that the heat block is protected from vibration during testing of bacterial endotoxin via the gel clot test method.

29. IntegratedreVIEW – Lab Q&A • How do we classify and approve or disapprove applications when the contract lab’s chemistry division is NAI/VAI and the microbiology division is OAI? • Is the firm require to have a stability indicating test method to test FP (not stability samples)? • Is testing for degradants required for FP testing?

30. F/E System – Quality by Design ISO 8/ISO 7 Hot Cell Red zone: LAFW/HCA Orange zone: clean room

31. F/E System – Facility 483’s • There is no written justification for setting hot cell’s viable microorganism monitoring action and alert levels higher than the surrounding clean room. • The alert and action levels are in conflict with SOP … titled “Environmental Control Policy”, Section 6.8.1 which states that “Red = The entire area where product and the containers are closures are exposed in aseptic processing (Hot Cell/LAFW), this area has the highest level of controls for access, gowning, cleaning, airborne particulate and microorganism levels.” Section 6.8.2 states “Orange = The area immediately surrounding the red zone (production rooms and enclosures). This area has high level of controls for access, gowning, cleaning, airborne particulates and microorganism levels.” • The alert/action limits for production room where the hot cell is located are established at 10/20 CFU per plate respectively while the alert/action limits for hot cell are established at 25/50 CFU per plate. The following results were recovered from inside the hot cell during 2014 after the build-out of the production room (Orange area) on … • Per SOP … titled “Total Aerobic Airborne Bioburden Form –LAFW”, the alert/action limits are ≥ 1 CFU/plate and > 3 CFU/plate respectively. Both hot cell and LAFW are considered Red Zone areas.

32. F/E System – Facilities 483 items21 CFR 211.42(c)(5) • Separate or defined areas to prevent contamination or mix-ups are deficient regarding the manufacturing and processing operations. Specifically, the firm has no written procedure(s) to address the containment of cytotoxic drugs during manufacturing to prevent cross contamination. For examples, • Cytotoxic drugs such as AAA, BBB, and CCC can be manufactured in non-cytotoxic rooms # 1, 2, 3, 4, & 5 where non-cytotoxic drugs are manufactured. • Non-cytotoxic drugs such as DDD and EEE can be manufactured in cytotoxic rooms # 6, 7, & 8 where cytotoxic drugs are manufactured. • Paperwork such as equipment use log, room use log, and batch records are not contained in the high containment areas. • There is no restriction for personnel accessing both high and non-high containment areas.

33. F/E System – Equipment 48321 CFR 211.63 Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use. Specifically, the firm does not have a procedure to assess the need for equipment re-qualification. For example, the following pieces of equipment used in the manufacture of drug products either were operating out of specification range or did not have adequate qualification information. 1. Coating machine XYZ: OOS’s for inlet air volumes were found during the coating of ABC products 50mg and 75mg delayed release tablets in different batches manufactured and inlet air volume results were not being compared to any specifications during the initial equipment qualification 2. Tray Dryer PE1: no mapping study was documented 3. Tray Dryer PE2: no mapping study was documented 4. Autoclave Q123 for micro use: no mapping study was documented and print-outs of autoclave cycle can be used without qualification to show that they match with actual cycle temperature and time

34. IntegratedreVIEW – F/E Q&A • Do reviewers evaluate manufacturing equipment scale up as part of QbD? • Is there any classification to the potency of potent drugs (i.e. chemo drugs) which translate into different containment requirements?

35. Production - DQRS • Friability Poor: Caregiver (patient's mother) reported that the tablets that were stored in the prescription vial disintegrated into powdery chunks and became unusable. Caregiver reported that the prescription vial was stored in a ziplock type bag with other vials of medicine (which are not affected), was not exposed to an excess of heat or humidity and could offer no explanation as to why this may have happened. • Friability poor: Opened a sealed bottle of #100 tablets & one tablet was in pieces. • Chipped: Several unit dose packages of ABC 5mg tablets - repackaged into unit dose blister packages by XYZ Packaging have been found to contain partial tablets.

36. Production 21 CFR 211.100(b) • In-process specifications are not derived from previous acceptable process average and process variability estimates where possible. Specifically, • The firm did not justify why it changed the order of charge-in components, mixing time, and mixing speed during the blending stage when it transferred the development work technology from its contract research lab to its facility. For example, • Contract research batch: mix ABC product with PVP K29/32 (100 mesh) for 2 minutes then add CMS-Na to the mixture and mix for 2 minutes. • Firm executed batch: charge ABC API, Povidone, and CMS-Na into a 1 cubic feet V-Blend and mix for 5 ± 3 minutes. • Firm’s proposed commercial batch: charge ABC API, Povidone, and CMS-Na into a 5 cubic feet V-Blend @ 30 ± 5 rpm and turn for 5 ± 3 minutes. • The firm did not justify why they did not use the mesh for delumping purpose during blending for the biobatch and proposed commercial batch which was used for the R&D batch at the contract research site. • Blending studies were not conducted to support the blending speed and time from development (15 rpm & 2 minutes) to the 13kg biobatch (30 rpm & 5 minutes) and to the 50kg commercial batch (30 rpm & 5 minutes) for 3 different size V-blenders: 5 L, 1 cu ft, and 5 cu ft respectively. • Coating (spray rate) was not studied during development both at the contract development lab and the firm. The firm did not set spray rate specification for the 13kg biobatch using the 15 inch coating pan. The firm set spray rate specification at 80-90 g/min for the 50kg proposed commercial batch using the 30 inch coating pan without coating (spray rate) study. • The firm did not define spraying time in both the biobatch and proposed commercial batch records.

37. Written distribution procedures are not established. Specifically, SOP-MA-021/001 titled “SOP of releasing export products” does not ensure that products shipped from Vietnam to US are protected under appropriate storage conditions to not alter the identity, strength, quality, and purity of the finished drug products (Rohto Cool, Ice, Arctic, and Hydra) under the current shipping conditions which are not monitored. IntegratedreVIEW – Production Q&A • How do investigators integrate reviewers’ comments such as tablet hardness, spraying rate, etc. into cGMP review?

38. Materials System21 CFR 211.84(d)(2) Each component is not tested for conformity with all appropriate written specifications for purity, strength, and quality. Specifically, A. The firm has not performed any full testing to qualify the supplier’s CoA’s for the following API’s: • AAA API, FCC • This API is used in the manufacture of XYZ Tablets • BBB API, USP • This API is used in the manufacture of DEF and GHI Tablets • CCC API, FCC • This API is used in the manufacture of DEF, GHI, and JKL Tablets

39. Materials System (cont.)21 CFR 211.84(d)(2)

40. Material System – Shipping21 CFR 211.150 • Written distribution procedures are not established. • Specifically, SOP-AAA titled “SOP of releasing export products” does not ensure that products shipped from Country X to US are protected under appropriate storage conditions to not alter the identity, strength, quality, and purity of the finished drug products (A, B, & C) under the current shipping conditions which are not monitored.

41. IntegratedreVIEW - Materials Q&A • Can firms use non-pharmaceutical grade ingredients if they qualify those ingredients by conducting full testing? • If an ingredient is a USP ingredient but supplier’s CoA of that ingredient has more tests listed in CoA (i.e. impurities), is the firm required to test them?

42. Quality – DQRS • Particulates: Noticed what appears to be fiberglass like particles in ABC product number 12345 fibers are roughly 1 inch in length. • Foreign material in dosage form: Pharmacy Technician discovered a foreign object (brick-colored, rubber-like piece) INSIDE an enclosed IV BAG of ABC product 500mL.

44. Quality System – Training21 CFR 211.25(a) • Employees engaged in the packing of a drug product lack the training required to perform their assigned functions. Specifically, • This employee’s training for … business line particulate matter inspection failed visual inspection tested on … at 50% (specification of 70% passing rate) but result recorded was 95% per SOP…titled “… Inspectors Training & Certification.” There is no line speed documented during the training of 200 bottles with 20 bottles with particulate matter to be picked out. This employee’s last passed training was on … with 80% passing result. • Five other employees were discovered to have “passing results” when they actually failed … visual inspection testing on date… as reported under Deviation # ... • Employee # 1 – failed at 60% but recorded as 96% passing • Employee # 2 – failed at 55% but recorded as 95.5% passing • Employee # 3 – failed at 65% but recorded as 96.5% passing • Employee # 4 – failed at 45% but recorded as 94.5% passing • Employee # 5 – failed at 60% but recorded as 96% passing

45. The Gold Standard ManufacturingIs high quality built into the process/product?

46. Embracing Quality Drug Product Experience – ADE, Mfg Quality, & Tampering issues