stability studies in pharmaceutical development Kathy Waddle, MS Wei Pan, Ph.D. RAC Catalent Pharma Solutions

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1 stability studies in pharmaceutical development Kathy Waddle, MS Wei Pan, Ph.D. RAC Catalent Pharma Solutions

2 Agenda Overview of stability studies during drug product Lifecycle Stability considerations during early development Review ICH and WHO stability guidelines Stability requirements to support registration Post approval stability Catalent Pharma Solutions 1

3 Importance of Product Stability Definition of Product Quality Free of contamination and reproducibly delivers the therapeutic benefit promised in the label to the consumer Definition of Stability Consistent product quality and therapeutic benefit over the product shelf-life under various environment conditions Consumer Expect Stability! - Gary Buehler, Director, OGD, FDA, AAPS SFG Stability Workshop, Sept 2007 Catalent Pharma Solutions 2

4 Stability Quality by Design Pharmaceutical product stability is a function of: Drug Substance Excipients Product Understanding Manufacturing Process Container Closure Catalent Pharma Solutions 3

5 Stability Studies During Pharmaceutical Product Lifecycle File IND File NDA Approval Drug Discovery Preclinical Phase I Phase II Phase III Final Labeling Discussions Phase IV PLCM Rx to OTC Stability studies to support formulation development and clinical studies Stability studies to support marketing application Stability studies to monitor product quality and support post approval changes Catalent Pharma Solutions 4

6 Stability Considerations During Early Development Limited regulatory requirement conduct stability studies to demonstrate clinical trial materials meet specifications during the course of trial Stability studies are done to gain understanding of the compounds/formulation in development Chemical and physical property of API Excipient compatibility Manufacturing process Interaction with packaging materials Catalent Pharma Solutions 5

7 Stability Considerations During Early Development API + Manufacturing Process DRUG PRODUCT Packaging Selection PACKAGED PRODUCT ECIPIENTS Catalent Pharma Solutions 6

8 API Mechanisms of Instability - Chemical Identify functional groups and labile centers 2º and 3º Amines --> N-oxide, hydroxylamine by oxidation Aldehyde --> Acid by oxidation Esters/Lactones -->Acid/Alcohol by hydrolysis Consider external contributing factors ph, temperature, humidity, light Perform forced degradation studies Acid/base Heat Oxidation Photolysis Understand mechanisms of degradation of drug substance Catalent Pharma Solutions 7

9 API Mechanisms of Instability - Physical Polymorphs Polymorphic transition Hydrate/solvate formation Dehydration/desolvation Crystallization of amorphous materials Particle size/surface area Other quality attributes Resuspendibility Aggregation Catalent Pharma Solutions 8

10 Excipient Compatibility ICH Q8 guidance recommends evaluating drug-excipient interactions as part of the design of a stable formulation. For solutions and suspensions, the solution studies indicate which buffer to use and the optimum ph. For solids, the compatibility studies are more extensive with the objective to establish which excipients can be used with the intended drug. - Binary excipients compatibility studies - Trial formulations (DOE) - Q8(R2): Pharmaceutical Development, Nov 2005 Catalent Pharma Solutions 9

11 Case Study 1 An compound with a carboxyl functional group is the candidate for a HFA MDI formulation development. Due to poor aqueous solubility, ethanol was chosen as co-solvent and the experimental formulation was put on accelerated stability. A degradant peak was observed and it reached >3% at 3 month time point. The sample was send to the LC-MS lab for peak ID. Question: What is the structure of the degradant? Answer: it s the ethyl ester of the API. Hint: Know your chemistry. Catalent Pharma Solutions 10

12 Case Study 2 Trace level of Aldehydes in common excipients Cause of gelatin cross-linking Reactive with primary and secondary amine Present as trace level impurities or formed by excipient degradation (e.g. PEG or Tween) -Leonardo Allain and W. Peter Wuelfling, Merck Research Labs, AAPS Stability Workshop, 2009 Catalent Pharma Solutions 11

13 Case Study 2 Catalent Pharma Solutions 12

14 Case Study 2 Compendial: PVP and Ethylcellulose in USP Wet chemistry techniques (one is enzymatic and the other is colorimetric) 100 ppm limit test 100 ppm formaldehyde ~ 10% API (mol/mol) (assuming 0.5 g formulated drug with 2-5% drug load) LOD of Merck GC derivatization method: 0.1 ppm Catalent Pharma Solutions 13

15 Case Study 2 Excipients Formaldehyde (ppm) Avicel 1.1 HPMC 12.3 PEG PEG Tween Triglycerides 0.2 Polyoxyl Opadry white 4.7 Kollicoat 13.7 Catalent Pharma Solutions 14

16 Manufacturing Process Choose manufacturing conditions to improve stability - Exposure to solvents Exposure to temperature - Drying time and temperature Stability of in-process materials Drug Product may be tested to identify critical process parameters Catalent Pharma Solutions 15

17 Container Closure Systems Linked to mechanisms of instability Does it need to be protected from light or moisture? Potential drug absorption or adsorption to container closure Effect of container orientation Potential for leachables container, closure, glue and ink Catalent Pharma Solutions 16

18 Case Study - Stability of Sterile Product M in Glass and Plastic Packages Catalent Pharma Solutions 17

19 Stability Studies During Pharmaceutical Product Lifecycle File IND File NDA Approval Drug Discovery Preclinical Phase I Phase II Phase III Final Labeling Discussions Phase IV PLCM Rx to OTC Stability studies to support formulation development and clinical studies Stability studies to support marketing application Stability studies to monitor product quality and support post approval changes Catalent Pharma Solutions 18

20 Stability Studies for Registration the purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and to establish a retest period for the drug substance or a shelf-life for the drug product and recommended storage conditions -ICH Q1A(R2): Stability testing of new drug substance and product (2003) Catalent Pharma Solutions 19

21 Stability Guidelines ICH (US, Japan, EU) WHO Regional US: FDA (1998 draft and 1987 guidance withdrawn, June ) EU: EMEA (European Medicines Agency), CPMP Japan: MHLW (Ministry of Health, Labor and Welfare: Drug Approval and Licensing Procedures in Japan, 2008) ASEAN (Association of Southeast Asia Nations) Brazil (Resolucao-Re No 1, July 29, 2005) China (Chinese Pharmacopeia 2005) SADC (Southern African Development Community), Medicines Control Council: Stability January 2005 Catalent Pharma Solutions 20

22 FDA Stability Guidelines FDA withdraws stability and CMC information related guidance documents on June 1, 2006: Not because following them will lead to problem with drug registration But because these documents are overly prescriptive, which is not consistent with the FDA s current thinking of providing broad guidance In the meantime refer to the following ICH documents as alternative resources Catalent Pharma Solutions 21

23 Stability Studies to Support Global Registration In order to be able to reduce the amount of stability testing required, the number of different long-term testing conditions must be reduced to a sufficient extent. This approach was proposed by Paul Schumacher in 1972 (1) and by Wolfgang Grimm in 1986 (2), and in 1998 (3) when they defined four different long-term testing conditions, which match with the climatic conditions of the target markets categorized in just four different climatic zones. -WHO Technical Report Series, No. 953, 2009: Stability testing of active pharmaceutical ingredients and finished pharmaceutical products Catalent Pharma Solutions 22

24 ICH Guidelines Founded 1990 ICH region European Union, Japan and US Regulators and pharmaceutical industry representatives Stability was one of the first issues discussed and harmonized Step1 Step1 Step2 Step2 Step3 Step3 Step4 Step4 Step5 Step5 Consensus building by EWG Consensus Agreed six parties Regulatory Consultation Adopt Implement Catalent Pharma Solutions 23

25 ICH Stability Guidelines ICH Stability Guideline Q1A(R2): Stability Testing of New Drug Substances and Products (Second Revision) Reached implementation step (step 5) in the ICH Tripartitate Region EU : Adopted by CPMP, March 2003, issued as CPMP/ICH/2736/99 MHLW : Adopted June 3, 2003, PFSB/ELD Notification No FDA : Published in the Federal Register, Vol, 68, No. 225, Friday, November 21, 2003; pages Also adopted by some non-ich countries including Canada, Australia Switzerland Catalent Pharma Solutions 24

26 ICH Stability Guidelines The Four Climate Zones: Zone I Temperate 21ºC±2ºC /45%RH ±5%RH Zone II Subtropical & Mediterranean 25ºC±2ºC/60%RH ±5%RH Zone III* Hot & Dry 30ºC±2ºC/35%RH ±5%RH Zone IV* Hot & Humid 30ºC±2ºC/65%RH ±5%RH * Q1F: Stability Data Package for Registration Applications in Climatic Zones III and IV was withdrawn June 2006 and decided to leave definition of storage conditions in Climatic Zones III and IV to the respective regions and WHO. Catalent Pharma Solutions 25

27 World View of Climatic Zone Determinations by Country Catalent Pharma Solutions 26

28 ICH Stability Guidelines Catalent Pharma Solutions 27

29 ICH Stability Guidelines Catalent Pharma Solutions 28

30 WHO Stability Guideline 193 Member States Split Climate Zone IV (hot and humid) to two zones - Climate Zone IVA (hot & humid) 30ºC/65%RH - Climate Zone IVB (hot & very Humid) 30ºC/75%RH Evaluation of climate condition by each Member State results in the recommendation of long term storage conditions More severe conditions are acceptable -WHO Technical Report Series, No. 953, 2009: Stability testing of active pharmaceutical ingredients and finished pharmaceutical products Catalent Pharma Solutions 29

31 WHO Stability Guidelines at a Glance Catalent Pharma Solutions 30

32 WHO Stability Guideline Additional Guidance Provided in WHO Document: Testing parameter recommendations Storage statement and labeling guidance Covers new drug and marketed product Catalent Pharma Solutions 31

33 WHO Stability Guideline Catalent Pharma Solutions 32

34 Stability Studies During Pharmaceutical Product Lifecycle File IND File NDA Approval Drug Discovery Preclinical Phase I Phase II Phase III Final Labeling Discussions Phase IV PLCM Rx to OTC Stability studies to support formulation development and clinical studies Stability studies to support marketing application Stability studies to monitor product quality and support post approval changes Catalent Pharma Solutions 33

35 Key Elements of a Stability Protocol 21CFR (a) There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include: Sample size and test intervals Storage condition Reliable, meaningful and specific test methods Store the drug product in the proposed container for marketing Testing of drug product for reconstitution at time of dispensing as well post reconstitution Catalent Pharma Solutions 34

36 Key Elements of a Stability Protocol Purpose (R&D, NDA, ANDA, Commercial, etc) Regulatory compliance/intended Market (US, EU, Global, etc) Name of the product and dosage strengths Container closures (and orientations, if applicable) Test methods and specification Storage condition and test intervals Sampling plan Bracketing and/or matrixing rational (if utilized) Data reporting and statistical analysis (proposed) Signature and change control Proposed expiration dating period Catalent Pharma Solutions 35

37 Container Closure Systems Solid Orals US HDPE bottles PVC, PVC/PVDC, or ACLAR blisters Bulk Storage/bulk sales - Double PE bags - PET/PE/Aluminum Foil/PE Barrier bags Solid Orals Europe Primarily PVC, PVC/PVDC blisters Often opaque rather than clear blisters - color: white, blue or green Catalent Pharma Solutions 36

38 Container Closure Systems Climate Zone 4 Solid Orals Glass or HDPE Bottles Blister - Cold-formed aluminum foil-foil blister - PVC, PVC/PVDC or ACLAR blister - Only for moisture insensitive, stable dosage forms Regional Solid Oral Simple blister with Al/PE film over wrap Glass bottle Catalent Pharma Solutions 37

39 Test Methods/Specifications Q6 : Specifications for New Drug Substances and Products - Q6A: Specifications: Chemical Substances, Oct Q6B: Specifications: Biotechnological/Biological Products, March 1999 Q2(R1): Validation of Analytical Procedures: Text and Methodology, Oct 1994 Q3A(R2): Impurities in New Drug Substances (Revised Guideline) Oct 2006 Q3B(R2): Impurities in New Drug Products (Revised Guideline) June 2006 Q1E : Evaluation of Stability Data, February 2003 Catalent Pharma Solutions 38

40 Example 1 A Really Simple Stability Protocol Tablets in 30-count HDPE bottle for US market Condition Initial 3M 6M 9M 12M 18M 24M 36M Total Stored 25ºC/60%RH [2] [2] [2] [2] [2] [2] [2] [2] 24 30ºC/65%RH - [2] [2] [2] [2] () () () () ºC/75%RH - [2] [2] = Appearance (n=1), Assay/RS (n=2),dissolution (n=6), Water Content (n=2) [ ] = number of bottles pulled ( ) = Optional testing only when significant changes occurs under accelerated conditions Catalent Pharma Solutions 39

41 Definitions of Significant Change 1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures. 2. Any degradation product s exceeding its acceptance criterion. 3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test. 4. Failure to meet the acceptance criterion for ph; or 5. Failure to meet the acceptance criteria for dissolution for 12 dosage units. -ICH Q1A(R2) Catalent Pharma Solutions 40

42 Example 2 a Simple Stability Protocol Tablets in 30-count HDPE Bottle for Global Registration Condition Initial 3M 6M 9M 12M 18M 24M 36M Total Stored 25ºC/60%RH [2] [2] [2] [2] [2] [2] [2] [2] 24 30ºC/65%RH - [2] [2] [2] [2] [2] [2] [2] 22 40ºC/75%RH - [2] [2] = Appearance (n=1), Assay/RS (n=2),dissolution (n=6), Water Content (n=2) [ ] = number of bottles pulled Note: There is no intermediate condition for Zone III/IV Catalent Pharma Solutions 41

43 Example 3 - a Complicated Stability Protocol Sterile product in glass vials for US market (store inverted) Condition Initial 3M 6M 9M 12M 18M 24M 36M Total Stored 25ºC/60%RH [4] [4] [4] [4] [50] PSL [4] [50] PSL [50] PSL ºC/65%RH - [4] [4] [4] [50] () () () (PSL) ºC/75%RH - [4] [14] PL = Appearance including color and clarity, Assay/RS, Preservative content, ph P = Particulate matter by HIAC S = Sterility, Bacterial Endotoxin, Antimicrobial effectiveness, Container Closure integrity L = Leachables [ ] = number of bottles pulled ( ) = Optional testing only when significant changes are observed under accelerated conditions Catalent Pharma Solutions 42

44 Example 4 an Even More Complicated Stability Protocol Sterile Product in a Semi - permeable Containers for Us Market Condition Initial 3M 6M 9M 12M 18M 24M 36M Total Stored 25ºC/40%RH [4] [4] [4] [4] [50] PSL [4] [50] PSL [50] PSL ºC/65%RH - [4] [4] [4] [50] () () () (PSL) ºC/20%RH - [4] [14] PL = Appearance including color and clarity, Assay/RS, Preservative content, ph P = Particulate matter HIAC S = Sterility, Bacterial Endotoxin, Antimicrobial effectiveness, Container Closure Integrity L = Leachable, [ ] = number of bottles pulled ( ) = Optional testing only when significant changes are observed under accelerated conditions Catalent Pharma Solutions 43

45 Example 4 an Even More Complicated Stability Protocol Sterile Product in Semi -permeable Containers for US Market Condition Initial 3M 6M 9M 12M 18M 24M 36M Total Stored 25ºC/40%RH [10] W [10] W [10] W [10] W [10] W [10] W [10] W [10] W 10 30ºC/65%RH - [10] [10] [10] [10] (W) (W) (W) (W) ºC/20%RH - [10] [10] W W W = Weight Loss (n=10) Note1 : The same 10 units are used for weight loss test as in-and-out of the chamber stability samples. The stability coordinator and lab analyst need to coordinate testing to minimize the time the samples are out of the chamber. Note 2: A 5% loss in water from its initial value is considered a significant change for a product packaged in a semi-permeable container after an equivalent of 3 months storage at 40 C/NMT 25% RH. Catalent Pharma Solutions 44

46 Batch Selections Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied. At least three primary batches Final formulation Manufacturing process simulating production batch Product with same quality and meeting same specification In container closure system as proposed for marketing At least two of the three are pilot scale* The third batch can be smaller, if justified Using different batches of API (if possible) * For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger. Catalent Pharma Solutions 45

47 Stability Data at Submission For NDAs: Three primary batches 12 months long term 6 months accelerated 6 months intermediate if significant accelerated May statistically project expiry up to 6 months past real time data For ANDAs One batch 3 months accelerated 3 months satisfactory accelerated data may permit 24 month expiry Catalent Pharma Solutions 46

48 Other Stability Studies In-use stability Minimum of two batches At beginning and toward end of shelf-life Photostability One batch In the proposed container and closure systems ICH Q1B option 1 or option 2 Thermocycling or excursion study Catalent Pharma Solutions 47

49 Stability Data at Submission Based on the data and product understanding, a sponsor should provide: Proposed expiration dating period and justification Proposed label storage condition and justification Proposed in-use label storage condition and in-use time period and justification, if applicable Stability Data Product Understanding Product shelf-life and Storage Conditions Catalent Pharma Solutions 48

50 Stability Commitment When available long term stability data on primary batches do not cover the proposed shelf life granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the shelf life. Submission data from 3 production batches, continue long term study through proposed shelf-life. Submission data from <3 production batches, set more production batches on to make up the required three with same protocol. Submission data not from production batches, first 3 production batches to set on stability through proposed shelf-life long term and 6 months accelerated. Catalent Pharma Solutions 49

51 Stability Studies During Pharmaceutical Product Lifecycle File IND File NDA Approval Drug Discovery Preclinical Phase I Phase II Phase III Final Labeling Discussions Phase IV PLCM Rx to OTC Stability studies to support formulation development and clinical studies Stability studies to support marketing application Stability studies to monitor product quality and support post approval changes Catalent Pharma Solutions 50

52 Stability Studies Post Approval After approval, routine stability study is conducted to monitor product quality Only long term condition is required Can drop testing point from standard ICH (through PAS) Can be used to extend expiry (through annual report) May want to add a expiry test point Stability failure can result in field alert* and/or product recalls 21CFR Sponsors are required to report to FDA district office within 3 working days of a problem being identified. Catalent Pharma Solutions 51

53 Stability Studies for Post-Approval Changes change in the manufacturing process; change in the composition of the formulation; change of the immediate packaging; change in the manufacturing process of an API. Additional stability testing (3 or 6 months long term and accelerated) are often required to support the changes. Catalent Pharma Solutions 52

54 Stability Studies for Post-Approval Changes US EU Major Changes Substantial potential to have an adverse effect Type II Moderate Changes Moderate potential to have an adverse effect Type IB Minor Changes Minimal potential to have an adverse effect Type IA Catalent Pharma Solutions 53

55 Stability Studies for Post-Approval Changes 1. FDA/CDER (November 1995) Guidance for industry Scale up and post-approval changes: immediate release solid oral dosage forms. 2. FDA/CDER (September 1997) Guidance for industry Scale up and post-approval changes: modified release solid oral dosage forms. 3. FDA/CDER (May 1997) Guidance for industry Scale up and post-approval changes: non-sterile semisolid dosage forms. 4. FDA/CDER (January 1999) Guidance for industry Scale up and post-approval changes: immediate release and modified release solid oral dosage forms manufacturing equipment. 5. FDA/CDER (April 2004) Guidance for industry Changes to an approved NDA and ANDAs. 6. CHMP/CVMP (December 2005) Guideline on stability testing for applications for variations to a marketing authorization CPMP/QWP/576/96 Rev 1 EMEA/CVMP/373/04 7. EMEA (2006) Guideline on dossier requirement for Type IA and IB notification 8. WHO (February 2007) Annex 6 variation guidance: guidance on variation to a prequalified product Dossier Catalent Pharma Solutions 54

56 discover more. CATALENT PHARMA SOLUTIONS 14 SCHOOLHOUSE ROAD SOMERSET, NJ

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