Risk-based analysis in pharmaceutical procurement and market analysis

1. Risk-based analysis in pharmaceutical procurement and market analysis Vivienne Christ Therapeutic Goods Administration Australia Interregional Seminar for Quality Control Laboratories involved in WHO Prequalification Programme and/or participating in respective sampling and testing projects, Nairobi, Kenya, 23-25 September 2009

2. Outline • Pharmacopoeial and other tests • General requirements • Microbiological and chemical tests • Tests for various dosage forms • Risk assessment (analysis) • An approach to targeted sampling and testing • Example of a risk-based assessment • To assist your with hands-on exercise

3. Pharmacopoeial and other tests • British Pharmacopoeia (BP) • European Pharmacopoeia (Ph Eur) • United States Pharmacopeia (USP) • International Pharmacopoeia IP) • Other validated methods (ISO17025, ICH Guideline) • ICH Tripartite Guideline Validation of Analytical Procedures: Text and Methodology Q2(R1) http://ich.org/LOB/media/MEDIA417.pdf

4. General monograph requirements • Visual examination • Packaging • Labelling • Product appearance, particulates, integrity • Storage conditions • Microbiological tests • Sterile products • Test for sterility and endotoxin test for parenterals • Non-sterile products • Microbial attributes tests • Chemical tests

5. Microbiology laboratory

6. Microbiological testing • Sterility testing • Endotoxin testing • Microbial attributes • Total aerobic microbial count (TAMC) • Presence/absence testing • Preservative efficacy testing • Microbiological bioassay for potency • Eg. nystatin, gentamicin • Disinfectant efficacy testing

7. Chemistry laboratory

8. Chemical tests • Uniformity of mass, - dose, - content • Disintegration and Dissolution tests • pH and moisture content • Presence of heavy metals • Identity tests • IR spectrophotometry, TLC + UV detection • Colorimetry • Absorption spectrum (AA) • Optical rotation (useful for natural products) • Assay of active(s) • HPLC, UV, AAS, GC (for volatiles) • Related substances for organic chemicals • For process impurities and degradation products (HPLC, TLC) • Organic volatile impurities (GC)

9. Access to Chemical Reference Substances • Pharmacopoeial CRS • International Chemical Reference Substances (ICRS) • Used to validate test methods and test results • Used as primary standard to calibrate secondary standards

10. Dosage forms • Parenteral products • Ophthalmic products • Oral dosage forms • Tablets, capsules, powders • Rectal products • Suppositories • Inhalation and nasal products • Topical products • Creams, gels • Ointments • Transdermal patches • Suppositories, pessaries

11. Parenteral products (SVP & LVP) • Supplied as • Vials, ampoules, bottles, bags, pre-filled syringes, etc • Solutions, freeze dried powders or emulsions • Single or multidose presentations • Test for Sterility • Terminal sterilization? Parametric release? • Aseptic processing? • Pharmacopoeial bacterial endotoxin/pyrogen test • LAL test • Pharmacopoeial microbiological bioassay for potency • eg vancomycin • Pharmacopoeial preservative efficacy test for all multidose presentations • Closed shelf-life testing (developmental and at expiry) • Open-shelf life testing to support in-use life if > 24 hours

12. Parenteral products (SVP & LVP) • Chemical tests • Powders for reconstitution: • Uniformity of mass for single dose preparation • Moisture content (Karl Fischer or LOD) for antibiotics, etc • Uniformity of content • pH of solutions • Particulate matter • Preservative content assay • Identity, assay and related substances • HPLC • Extractable volume for SVP

13. Ophthalmic (eye) products • Supplied as • Sterile liquid, semi-solid, or solid preparations • Presented as eye drops and ointments • Usually aseptic manufacturing process • Quality of WFI? • Test for Sterility • Preservative efficacy if multidose • Closed shelf-life testing (developmental and at expiry) • Open-shelf life testing to support in-use life if > 24 hours • Microbiological bioassay • eg gentamicin eye drops • Particle size • Chemical tests • pH, • Identity • Assay and related substances by HPLC • Composition for antibiotics by HPLC

14. Inhalation products • Depends on presentation • Pressurised metered dose inhalers (MDI) • Dry powder inhalers • Products for nebulization • Non-pressurised metered dose inhalers (MDI) • Sterile single dose presentations preferred • Test for sterility for single dose products for nebulization • Microbial attributes for all non-sterile products • PET for multidose products for nebulization and non-pressurised MDIs • Chemical tests • Moisture content, mean delivered dose, uniformity of delivered dose, uniformity of content (single dose), particle size distribution (twin impinger or impactor), leak rate for pressurised MDI • Assay of quantity of drug substance

15. Nasal products • Microbial attributes • TAMC, presence/absence testing • Preservative efficacy • Closed shelf-life testing (developmental and at expiry) • Chemical tests • As for parenteral solutions

16. Oral medicines - Liquids • Microbial attributes • TAMC, absence/presence testing • Test for Sterility • Eg sterile paediatric oral antibiotic products and some oral products for HIV/AIDS patients • Preservative efficacy • Closed shelf-life testing (developmental and at expiry) • Open-shelf life testing to support in-use life if > 24 hours • Bioassay • Potency of nystatin oral suspension • Chemical tests • pH • Identity • Assay and related substances • Preservative content

17. Oral Medicines - Tablets and capsules • Hard, soft and modified release capsules • Uncoated, coated and modified release tablets • Modified release – extended or delayed? • Micro-encapsulation process to modify rate of release in GI tract • Microbial attributes • Gelatin used in capsule shell • Not usually necessary as tablets have low Aw • TAMC, absence/presence testing

18. Oral Medicines - Tablets and capsules • Chemical tests • Uniformity of mass if active >5% of mass per IP • Uniformity of content if active is <5% of total formulation per IP • Disintegration test – not required if dissolution test is required • Dissolution test • Enteric coated delayed release: dissolution testing at low gastric pH 2 and higher intestinal pH 6.8 • Modified release: dissolution test over intended period (eg 24 hours) • Identity tests • Related substances test • Assay if uniformity of content does not apply

19. Rectal preparations • Suppositories • Uniformity of mass for single-dose preparations • Uniformity of content if active <2% of total mass (IP) • Microbial attributes • TAMC, presence/absence tests • Chemical tests • Disintegration • Identification • Assay and related substances

20. Topical medicines – Creams & gels • Hydrophobic or hydrophilic preparations applied to skin or mucous membranes • Sterile or non-sterile • Test for sterility • Sterile creams used on burns and open wounds • Microbial attributes • TAMC, presence/absence tests • Microbial Bioassay • nystatin • Preservative efficacy • Closed shelf-life testing (developmental and at expiry) • Open-shelf life testing to support in-use life if > 24 hours • Chemical tests • pH • Identity • Assay and related substances • Preservative content • Composition (including homogeneity) by HPLC

21. Topical medicines – Transdermal patches • Microbial attributes • TAMC, presence/absence (patch and backing material) • Chemical tests • Release tested with a suitable dissolution test • Active released per surface area per time unit • Method: disc assembly, cell or rotating cylinder (drum) depending on composition, dimensions and shape • Ph Eur “Dissolution test for transdermal patches” • Uniformity of content • Identity • Assay and related substances

22. Topical medicines - Ointments • Low Aw • Bioassay • Eg nystatin • Preservative efficacy not required due to low Aw • Chemical tests • As for creams and gels • Need to extract active by heating

23. Risk Management Overview

24. Risk-management? • AS/NZS 4360:2004 – Risk management standard & HB 436 • Available from www.standards.com.au • ISO/FDIS 31000:2009 – 1st draft based on AS/NZS 4360:2004 • ISO/IEC Guide 73 Risk Management – Vocabulary – Guidelines for use in standards “Although the concept of risk is often interpreted in terms of hazards or negative impacts, this Standard is concerned with risk as exposure to the consequences of uncertainty, or potential deviations from what is planned or expected. The process described here applies to the management of both potential gains and potential losses.” “Organizations that manage risk effectively and efficiently are more likely to achieve their objectives and do so at lower overall cost.” “Risk management is aiming to make optimal decisions in the face of uncertainty”

27. What do we mean by risk? • Risk can be defined as the combination of the probability of an event and its consequence • Risk assessment is the overall process of risk analysis and risk evaluation • In the health safety field consequences are generally only negative and the management of safety risk is focused on prevention and mitigation of harm

28. Risk Management Process – Overview Monitor and Review Communicate and Consult Establish the Context Identify Risks Risk Assessment Analyse Risks Evaluate Risks Treat Risks Adapted from AS/NZS 4360 2004

29. Risk Management Process – Overview Monitor and Review Communicate and Consult Establish the Context Identify Risks Risk Assessment Analyse Risks Evaluate Risks Treat Risks Adapted from AS/NZS 4360 2004

30. Risk Management Process – Detail Communicate and Consult Evaluate Risks Identify Risks What can happen? When and where? How and why? Establish the Context Internal Context External Context Risk Management Context Develop the Criteria Define the Structure Treat Risks Identify options Assess options Prepare and implement treatment plans Analyse and evaluate residual risk Analyse Risk Identify existing controls Compare against criteria Set priorities Determine Likelihood Determine Consequences Treat Risks YES Determine levels of risk NO Monitor and Review Adapted from AS/NZS 4360 2004

31. Establish the context • Communication and consultation • Consultation is a process not an outcome • impacts on a decision through influence • about inputs to decision-making • With whom do you need to consult and communicate? • List external organisations and individuals • List internal individuals • Formalise this process • Document it!

32. Medicine testing - Risk assessment team • Clinical experts • Pre-market assessors/evaluators • GMP experts • Adverse event reporting for the product • Complaint and recall histories for the product • Supply chain advisors • Surveillance and counterfeit advisors • Laboratory technical experts • Consumers and community groups

33. Risk assessment - Identify risks If something happens, then it might lead to an outcome, which might have an impact on public health due to the quality, safety or efficacy of a medicine • Questions • What can happen? • Where can it happen? • When can it happen? • Why it can happen? • How can it happen? • Tools and techniques depend upon the purpose of the risk management study and include: • Checklists • Judgements based on experience and records • Flow charts • Brainstorming • Systems analysis • Scenario analysis and systems engineering techniques (eg fault analysis)

34. Identify risks • A source of risk or hazard • An event or incident • A consequence, outcome or impact • A cause (what and why) • When and where could the risk occur • Controls and effectiveness

35. Analyse risks • Develop and understand the risk • Consider the source of risk • Consider both positive and negative consequences • Consider the likelihood that consequences might occur • Identify factors that affect consequences and likelihood • Analyse risk by combining consequences and likelihood • Take into account existing controls

36. Evaluate risks • Compare against your defined criteria • Consider balance between potential benefits and adverse outcomes • Set priorities • In terms of the extent and nature of treatments required • What tests can your laboratory target to increase the likelihood of detecting a substandard medicine in order to prevent an adverse event occurring? Performing a risk assessment is an iterative process

37. Types of risk analysis • Qualitative analysis • Words describes the magnitude of potential consequences and the likelihood that they will occur – eg high, medium, low risk • Informed by factual information and data where available • Semi-quantitative analysis • Descriptive words are given values (1= low, 10 = high) • Quantitative analysis • Numerical values “Particular care must be taken with quantitative analysis when examining consequences that are intangible or difficult to quantify such as environmental or safety effects or reputation” (AS/NZS 4360:2004) Check sensitivity of the method

38. Treat risks • Identify options • Assess options • Prepare and implement treatment plans • Analyse and evaluate residual risk

39. Monitor and review • Monitor effectiveness of risk management process • Ensure priorities have not changed

40. TGA

41. TGA’s targeted testing approach • Service Level Agreements (SLA) define annual lab testing program • Prescription Medicines Regulator • Includes drugs, plasma products, vaccines, biologicals, blood and tissues • Over-the-Counter (OTC) Medicines Regulator • Complementary Medicines Regulator • Medical Devices Regulator • Non-discretionary sample testing (urgent or priority) • Usually unplanned from an operational viewpoint • Discretionary sample testing (routine) • Amenable to operational planning • Based on an agreed risked-based sampling program

42. TGA’s testing priorities • Non-discretionary testing • Problem and complaint investigations • Adverse reactions • GMP alert samples • International alerts • Referral as a result of surveillance seizures • Suspect counterfeits • Urgent or high priority according to set performance timeframes • Discretionary testing • Compliance monitoring of products on the market • Selection of marketed products according to risk assessment • Usually includes a random selection of a small percentage of products • Product surveys conducted to maximise resources • Routine testing according to a monitored performance timeframe

43. Targeted testing • Level of risk associated with medicine itself • Intrinsic toxicity of the medicine • Likelihood of treatment failure if the medicine is ineffective • Medicine failure due to likelihood of deficiencies in quality • eg if product is difficult to make, or often poorly made • Other concerns about quality, safety, efficacy • Surveillance activity • Reports of adverse consumer reactions • Quality problems identified during manufacturer audits • Literature reports and international concerns

44. Factors that might affect the level of risk • The quality of the manufacturing process • The history of the manufacturer or sponsor • The potential for product to be contaminated with adventitious agents such as viruses and prions • Whether the product is intended to be sterile • Whether the product is an antibiotic, where potency may give rise to antibiotic-resistant strains • The natural propensity of the active constituent to instability, both molecular structure and pharmaceutic form (formulation) • The degree of exposure of the population to the product • The availability of counterfeit products in the market place, and • The outcome of other post-market activities

45. Formulating a risk-based testing plan • Consult Regulators, adverse reactions, surveillance, recalls, and GMP areas • Products prioritised for testing after determining risk level • Example outcomes • High end of risk spectrum • Every batch of product tested • Comprehensive selection of tests applied to each batch • Medium risk range • Might be subjected to physical testing periodically • Narrower range of relevant tests applied • Lower end of risk spectrum • Might undergo review of every batch documentation without physical testing • Periodic review of batch documentation only

46. The risk assessment(Introduction to hands-on exercise)

48. Event consequence Table 1 (example)

49. Applied example for Capsule Product Xfrom Table 1 Capsule Product X:

50. Table 1(a) Risk category rankUse score from Table 1