risk-based analysis in pharmaceutical procurement and market analysis vivienne christ therapeutic...

Risk-based analysis in pharmaceutical procurement

and market analysisVivienne 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

Sampling and testing for Quality Control Laboratories, Nairobi, September 20092 |

OutlineOutline

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


Pharmacopoeial and other testsPharmacopoeial 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


General monograph requirementsGeneral 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


Microbiology laboratoryMicrobiology laboratory


Microbiological testingMicrobiological 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


Chemistry laboratoryChemistry laboratory


Chemical testsChemical 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)


Access to Chemical Reference SubstancesAccess 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


Dosage formsDosage 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


Parenteral products (SVP & LVP)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


Parenteral products (SVP & LVP)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


Ophthalmic (eye) productsOphthalmic (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


Inhalation productsInhalation 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


Nasal productsNasal products

Microbial attributes– TAMC, presence/absence testing

Preservative efficacy– Closed shelf-life testing (developmental and at expiry)

Chemical tests– As for parenteral solutions


Oral medicines - LiquidsOral 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


Oral Medicines - Tablets and capsulesOral 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


Oral Medicines - Tablets and capsulesOral 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


Rectal preparationsRectal 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


Topical medicines – Creams & gelsTopical 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


Topical medicines – Transdermal patchesTopical 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


Topical medicines - OintmentsTopical 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


Risk Management OverviewRisk Management Overview


Risk-management?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”

http://www.standards.com.au/


What do we mean by risk?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


Risk Management Process – OverviewRisk Management Process – Overview

Establish the Context

Identify Risks

Evaluate Risks

Analyse Risks

Treat Risks

Adapted from AS/NZS 4360 2004


Risk Management Process – OverviewRisk Management Process – Overview


Identify Risks

Evaluate Risks

Analyse Risks

Treat Risks



Risk Management Process – DetailRisk Management Process – Detail

Communicate and Consult

Monitor and Review


Internal Context

External Context

Risk Management Context

Develop the Criteria

Define the Structure

Identify Risks

What can happen?

When and where?

How and why?

Analyse Risk

Identify existing controls

Evaluate Risks Treat Risks

Identify options

Assess options

Prepare and implement treatment plans

Analyse and evaluate residual risk

DetermineConsequences

Determine Likelihood

Determine levels of risk

Compare against criteria

Set priorities

Treat Risks

YES

NO



Establish the contextEstablish 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!


Medicine testing - Risk assessment team 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


Risk assessment - Identify risksRisk 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)


Identify risksIdentify 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


Analyse risksAnalyse 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


Evaluate risksEvaluate 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


Types of risk analysisTypes 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


Treat risksTreat risks

Identify options

Assess options

Prepare and implement treatment plans

Analyse and evaluate residual risk


Monitor and reviewMonitor and review

Monitor effectiveness of risk management process

Ensure priorities have not changed


TGATGA


TGA’s targeted testing approachTGA’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


TGA’s testing prioritiesTGA’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


Targeted testingTargeted 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


Factors that might affect the level of riskFactors 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


Formulating a risk-based testing planFormulating 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


The risk assessment(Introduction to hands-on exercise)

The risk assessment(Introduction to hands-on exercise)

(1) Event Consequence Table (1=insignificant, 2=minor, 3=moderate, 4=major, 5=catastrophic)

Adverse Reactions

Clinical Issues

Manufacturing Aspects

Recalls Testing/other

Score Total

Rank(2) Event Likelihood: (eg rare, unlikely, moderate, likely, almost certain)

Event Likelhood

OutcomeRisk Rating

Risk Action

Comments:

Assessed by:

Date

Approved:

Product: (Proprietary name, generic name)

Rank Parameter

Presentation

Dosage FormsRegistration numbers


Event consequence Table 1 (example)Event consequence Table 1 (example)RankDescriptionParameter

Adverse ReactionsClinical Issues

Manufacturing aspects

RecallsTesting/other

1InsignificantNo or few reports of adverse events associated with product

Quality failures not of clinical significance

Current GMP licence with A1 rating. No reported problems. No evaluation issues.

Product never recalledNo substantiated complaint. No counterfeiting or illegal supply known. No testing failures.

2MinorProduct of minor concern to ADRU with few serious reactions

Quality failures of low clinical significance

A2 rating for last GMP audit. Medium risk manufacturer.

Class II or III Wholesale.

Class III Hospital or Retail level

Counterfeiting or illegal supply of low concern. Failed low concern quality issues (eg label)

3ModerateProduct of moderate concern to ADRU with a number of serious reactions

Quality failures of moderate clinical significance

A3 rating for last GMP audit. High risk manufacturer

Class I Wholesale

Class II Hospital

Class III Consumer

Counterfeiting or illegal supply of mod. concern. Failed mod. quality parameters (eg borderline potency)

4MajorProduct of major concern to ADRU and has been associated with a relatively small number of patient deaths or a significant number of adverse reactions

Quality failures of severe clinical significance

Unacceptable risk assigned by GMP auditors

Class I Hospital or Retail

Class II Retail or Consumer

High frequency counterfeiting, including overseas. Failed critical quality issues (eg dissolution)

5CatastrophicADRU has recommended regulatory action because of significant number of deaths or a large number of serious adverse reactions.

Manufacturer’s licence revoked or suspended due to critical deficiencies

Class 1 Retail or Consumer

Class 1 Hospital for Highly Specialised Drugs

Product failed critical quality parameters (eg sterility, wrong active)


Applied example for Capsule Product Xfrom Table 1

Applied example for Capsule Product Xfrom Table 1

RankTotal

Score

Parameter

Adverse Reactions

Clinical Issues

Manufacturing aspects

RecallsTesting/other

Product of minor concern to TGA’s Office of Medicines Safety Monitoring (OMSM) with few serious adverse reactions

Quality failures of low clinical significance

A1 rating for last GMP audit. Current licence. No previous reported problems or pre-market evaluation issues identified.

Product has never been recalled.

Counterfeiting or illegal supply is of low concern. Failed low concern quality issues (eg minor label issues)

?82 (Minor)2 (Minor)1 (Insignificant)1 (Insignificant)2 (Minor)

Capsule Product X:


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

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

Risk consequence scoreRisk Category Rank

5-10Insignificant

11-15Minor

15-19Moderate

20-23Major

23-25Catastrophic


Event likelihood Table 2 (example)Event likelihood Table 2 (example)RankDescriptionEvent Likelihood (examples only)

IRareProduct not distributed in your country. No previous testing failures. Product has never been recalled

No recent changed to manufacturing process, specifications or test procedures. Recent self-assessable change by manufacturer. Current manufacturing licence. No previous reported problems. No issues identified during pre-market evaluation stage.

IIUnlikelyProduct used infrequently (eg vaccines used by travellers, antivenoms). Testing failures more than 5 years ago.

Product has been subjected to a Level 1 Recall more than 3 years ago. Product subjected to a Level 3 Recall only in the last 5 years.

Recent minor change to manufacturing process, specifications, test procedures. Recent change of manufacturing site for excipients. Manufacturing problems more than 3 years ago.

IIIModerateProduct failed significant quality parameters in the last 2-5 years. (eg potency, impurities). Failed moderate quality parameters within last 2 years. Recent moderate change to manufacturing process. Specifications, test procedures. Recent change of manufacturing site for API. Manufacturing problems in last 3 years.

IVLikelyProduct failed significant quality parameters in last 2 years (potency, impurities, incorrect active present). Subject to a Level 1 or 2 Recall in the last 3 years.

Recent moderate change to manufacturing process, specifications, test procedures. Recent change of manufacturing site for API.

V(Almost)

Certain

Product administered to large proportion of population (eg National Childhood Immunization Program). Product subject of a Level 1 or 2 Recall in past 12 months. Significant adverse events reported in last 3 years. Stability studies indicate low thermal stability. Recent major change to manufacturing process, specifications, test procedures. Recent change of manufacturing site for API and previous problems notes with manufacturing process. Manufacturing audit is overdue or license has expired.


Risk ranking Table 3Risk ranking Table 3

Use the risk consequence score from Table 1(a) and the likelihood from Table 2

Remember the score from Consequence Table 1(a) is ‘Insignificant’Remember the score from Likelihood Table 2 is ‘V (Almost certain)’

Risk Category (from Table 1(a))

Likelihood (From Table 2)

InsignificantMinorModerateMajorCatastrophic

I (Rare)1361015

II (Unlikely)2591419

III (Moderate)48131822

IV (Likely)712172124

V (Almost certain)1116202325


Risk action Table 4 (example)Risk action Table 4 (example)

Example of level of Post-market compliance testing required.Remember score from Risk ranking Table 3 is ’11’

Risk RankingRisk RatingAction Required (TGA’s test groupings)

Over 23SevereUrgent laboratory testing/ investigation

17 to 22HighProduct(s) placed in Test Group 3: products requiring the highest level of post-market assessment.

)Batch release protocols examined for every batch and samples of every batch required, but not every batch is tested.(

11 to 16ModerateProduct(s) placed in Test Group 4: products requiring a moderate level of post-market assessment .

)Batch release protocols examined for every batch and samples requested periodically for testing.(

New products placed in Test Group 2 until acceptable consistency established. (Protocols and samples required for first 5 batches. 3/5 batches tested and if results satisfactory, then move to Test group 4).

0 to 10LowProduct(s) placed in Test Group 5: products requiring a lower level of post-market assessment.

)Protocols and samples might be requested occasionally.Annual requirement for a report of batches manufactured.Status reviewed ever 5 years.(

Note: Test Group 1 - Pre-Registration testing to facilitate method development and validation in quality control testing laboratory .

2 2 1 1 2 8Insignificant

V (almost certain)

Product X

Capsule

11

Moderate. Samples of first five batches tested (Group 2), then tested periodically (Group 4)

Target tests: visual, LOD, degradation products (related substances) by HPLC or TLC,

and dissolution profile .

V. Christ

1/0/2009

Oral2009001234


SummarySummary

Pharmacopoeial tests– General, microbiological and chemical tests– Tests for various dosage forms

Risk assessment (analysis)

TGA’s approach to targeted sample testing

Worked example of a risk-based analysis to target samples and testing to assist with the hands-on exercise


Questions???Questions???

risk-based analysis in pharmaceutical procurement and market analysis vivienne christ therapeutic...

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