Ensuring the Quality of Some Drug-Device Combination Products - FDA Perspective

Transcription

1 Ensuring the Quality of Some Drug-Device Combination Products - FDA Perspective PQRI Meeting, Rockville, MD Ramesh Raghavachari, Ph.D. Chief, Branch I, DPMA I, OLDP OPQ 03/23/2017

2 OFFICE OF PHARMACEUTICAL QUALITY Safety Quality CMC Efficacy Clinical Outcome 2

3 Quality information in the NDA Technical Assessment How does it link to the patient?

4 Examples Covered Here Transdermal Systems Pulmonary Delivery Devices Auto Injectors Considered drug/device combination products under 21 CFR 3.2 4

5 Review Function Review between CDER and CDRH will be based on which center is the lead center. This talk will cover only the combination products for which CDER (drug component) is the Lead. The issues discussed are based on real examples that we have encountered in the Agency. 5

6 Transdermal Systems 6

7 Common Types of Transdermal Systems Matrix Type/Drug in Adhesive Backing Layer Drug/Adhesive Layer Release Liner Skin Reservoir Backing Layer Drug Reservoir Rate-controlling Membrane Contact Adhesive Release Liner Skin Iontophoresis Microneedles 0.02 mm 0.5 mm 3 mm 15 mm Stratum Corneum Epidermis Dermis Subcutaneous 7

8 Manufacturing Process for a Matrix Drug Substance System Adhesives Excipients MIXER The system is either re-rolled or sent to die-cutting and pouching COATER Backing Membrane Release Liner OVEN 8

9 Why Transdermal Products Continuous, at least for one or more days of drug delivery Convenience to the patient Wear it and forget about it Continuous delivery especially useful to treat chronic pain 9

10 List of Potential Quality issues that impact TDS Stability: Drug Crystallization Drug substance/excipient migration Cold Flow Adhesion 10

11 Drug Dispersion Changes occurring in the formulation? 11

12 Stability Issues - Migration Adhesive 1 Drug in Adhesive 2 Adhesive 1 Adhesive 1 or Drug in Adhesive 2 Drug in Adhesive 2 12

13 Crystallization 13

14 Cold Flow Cold flow Release liner Pictures Compliments of Anna Wokovich, CDER, St. Louis, MO 14

15 Cold Flow Pictures Compliments of 15 Anna Wokovich, CDER, St. Louis, MO 3/14/

16 Pulmonary Delivery Devices An alternate delivery route Invariably for local action in the lungs. Systemic delivery (rare) through the lungs, not just to treat diseases of the lung Convenience to the patient 16

17 Current Inhaled Therapies a) P. Peri IFPAC 2014, Jan. 23, 2013; b) The global market for pulmonary delivery of drugs is expected to rise to a $44 billion/annum by 2018 (PRWeb, June 24, 2014 from BCC Research LLC, 49-2 Walnut Park, Wellesley, MA 02481) 17

18 Orally Inhaled Products for Local Action/Systemic Delivery Metered Dose Inhalers (MDIs) also known as inhalation aerosols Dry Powder Inhalers (DPIs) also known as inhalation powders Inhalation solutions/suspensions Use CDRH cleared generaluse nebulizers (devices) Inhalation Sprays HandiHaler TwistHaler Diskus All of these are Combination Products as per 21 CFR

19 Metered Dose Inhalers -Aerosol 19

20 Metered Dry Powder Inhalers ource=lnms&tbm=isch&sa=x&ved=0ahukewie- 5zrx6vSAhWF2SYKHZHoCl8Q_AUIBygC#tbm=isch&q=inhalers&* 20

21 Metered Dry Powder Inhalers 21

22 Metered Dry Powder Inhalers 22

23 Pre- Metered DPIs 23

24 Inhalation Spray 24 24

25 Issues in Inhalation Products Delivered Dose Aerodynamic Particle Size Distribution (APSD) Plume Geometry (in case of Aerosol activated and sprays) Extractable and Leachable Information Human Factors 25

26 Particle Size Distribution Aerodynamic Particle Size Distribution is performed using Andersen Cascade Impactor Apparatus Next Generation Impactors are becoming more popular A model for the lung inhalation process 3 to 7 microns typical size for effective delivery to the lungs 26

27 Plume Geometry 27

28 Photographs of an Inhalation Spray Aerosol Plume [From R. Dalby et al., Int. J. Pharm. 283 (2004) 1-9] 28

29 Gamma Scintigraphy of Dosing in Human Subjects Inhalation Spray MDI MDI w/spacer [From R. Dalby et al., Int. J. Pharm. 283 (2004) 1-9] 29

30 Extractable & Leachable Important for all the materials in the device that the drug product comes in contact with. The leachables can have an adverse impact on patients both short term and long term. Cannot be more than 1.5 µg maximum per day Necessary for the Dry Powder Inhalers Study of leachables in samples under long term stability conditions. 30

31 Human Factors How easy is it, for a person to use? Intuitive A range of population and age 31

32 Refer: Wall Street Journal Tuesday March 07, 2017, Article on Inhalers by Sumathi Reddy 32

33 Auto-Injectors Invariably for self administration Ease of Portability Immediate use Types of Medication Epinephrine for anaphylaxis Morphine for pain (for wounded soldiers during war) Atropine (antidote for nerve gas poisoning) Insulins- routine administration- maintenance of sugar levels in blood for diabetes 33

34 Different types of Auto injectors 4&source=lnms&tbm=isch&sa=X&ved=0ahUKEwie- 5zrx6vSAhWF2SYKHZHoCl8Q_AUIBygC#tbm=isch&q=auto+injectors&* 34

35 Approved Epinephrine Auto-Injectors (0.3 mg dosage strength shown) EpiPen and AG* Adrenaclick and AG* Auvi-Q *AG = Authorized generic 35

36 Common Considerations Cannot have device activation failures Dose delivered Stability of the active in the device Force to fire Safety issues- Lacerations (bent or broken needles) Serious infections Hold time Restraining young children during administration 36

37 Lacerations (bent and broken needles) In 2016, Brown et al.* described 25 cases of needle injuries in young children who struggled against an epinephrine auto-injector injection 20 lacerations, 4 stuck needles, average age: 3 years Brown JC, Tuuri RE, Akhter S, et al. Lacerations and Embedded Needles Caused by Epinephrine Autoinjector Use in Children. Annals of Emergency Medicine Mar;67(3): e8 please contact Julie Brown julie.brown@seattlechildrens.org for permission to share this image 37

38 Injection Hold Time Varies from product to product On the average not more than 10 seconds in many products Agency has recommended shortening the time for rescue medication 38

39 Conclusions For the given examples of drug device combination products Device plays a crucial role in the delivery of the drug Device housing the drug product for a long period as the primary container closure, impacts stability Dose delivered is crucial for the safety and effectiveness Failure of the device may lead to serious adverse events in patients under emergency situations 39

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41 Acknowledgements Dr. Caroline Strasinger Dr. Robert Berendt Dr. Craig Bertha Dr. Peter Stark Dr. Julie Brown, Seattle Children's Hospital OPQ Management Organizers of this meeting Thank you! 41