Overview Internal review

Slide 1 © PharmOut 2015

Overview – Internal review• Presentation title: PDE Derivation for APIs – Case Study Venlafaxine

• Track title: Contamination/ Toxicology

• Speaker: Andrew Bartholomaeus

• Date / Time: Tuesday

• Time allotted: 1:30 – 2:30

• Dot point overview:

• A worked case study deriving a PDE and OEL for venlafaxine

R I S K I D E N T I F I C A T I O N F O R

M A N U F A C T U R E I N S H A R E D F A C I L I T I E S

PDE Derivation for APIsCase StudyVenlafaxine

BartCrofts Scientific Services Pty Ltd

Prof. Andrew BartholomaeusSchool of Pharmacy, University of Canberra

Therapeutic Research Centre, School of Medicine, University of QueenslandCEO, BartCrofts Scientific Services Pty Ltd

Email; [email protected]


1 . C L E A R L Y I D E N T I F Y T H E A P I

2 . G A T H E R A V A I L A B L E D A T A S O U R C E S

3 . I D E N T I F Y T H E K E Y H A Z A R D S

4 . E S T A B L I S H A N D R A N K O R D E R T H R E S H O L D S

5 . I D E N T I F Y U N C E R T A I N T I E S

6 . C A L C U L A T E P D E


Stepping Through the Process

C H E M I C A L A N D G E N E R I C N A M E

M A N U F A C T U R E R S R E S E A R C H C O D E S


Step 1 Identify the API

Identify the APIWhat is it


Generic Name Venlafaxene

Chemical Name (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]

cyclohexanol hydrochloride or (±)-1-[α- [(dimethyl-amino)methyl]-p-methoxybenzyl]cyclohexanol hydrochloride

MW 313.87

Structure

Brand Name Effexor

code name WY-45030 Early studies may use the code so this is important when searching

the literature

What does it do


Venlafaxine is an antidepressant that inhibits the reuptake of both 5-hydroxytryptamine (serotonin; 5-HT) and noradrenaline (NA). It is somewhat more potent as an inhibitor of the reuptake of 5-HT than NA. Its potency to inhibit the reuptake of 5-HT is comparable to that of tricyclic antidepressants (TCAs) such as amitriptyline or imipramine, but it is less potent than these drugs at inhibiting the reuptake of NA. ie the drug is quite receptor specific so any value that is

protective of the primary receptor is protective of less sensitive receptors

What is the normal human therapeutic Dose range


Maximum approved dose 225 mg/day

Minimum initiation dose 37.5 mg/day

This is a dose that does not produce side effects, or only minor effects, in most people

Unlikely to be pharmacologically active

Used to build tolerance to the drug before ramping up dosage to a pharmacologically active dose

Minimum daily dose 75 mg/day

The minimum shown to be therapeutically effective in clinical trials

A clear “effect” dose


Step 2 Gather Available Data Sources

Sources of Data


European Medicines Agency EPAR (European Public Assessment Reports - Summary of submission and evaluation)

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124

Clinical reports – from mid 2016

US FDA Drugs@FDA

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

Australian TGA Product Information Documents

http://search-au.funnelback.com/s/search.html?collection=tga-artg

AusPARs (Australian Public Assessment Reports) https://www.tga.gov.au/browse-auspars-active-ingredient

Prescribing Medicine in Pregnancy http://www.tga.gov.au/prescribing-medicines-pregnancy-database

NIH TOXNET (collection of databases including DART, TOXLINE, HSDB)

http://toxnet.nlm.nih.gov/

DailyMed http://dailymed.nlm.nih.gov/dailymed/index.cfm

For Vitamins and Minerals use Nutrient Reference Values, Upper Levels Eg US IOM - http://ods.od.nih.gov/Health_Information/Dietary_Reference_Intakes.aspx Australian NHMRC - https://www.nrv.gov.au/

Abstracting data bases, eg MEDLINE, PUBMED

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

http://search-au.funnelback.com/s/search.html?collection=tga-artg

https://www.tga.gov.au/browse-auspars-active-ingredient

http://www.tga.gov.au/prescribing-medicines-pregnancy-database

http://toxnet.nlm.nih.gov/

http://dailymed.nlm.nih.gov/dailymed/index.cfm

http://ods.od.nih.gov/Health_Information/Dietary_Reference_Intakes.aspx

https://www.nrv.gov.au/

Notes on Sources


No one source will give you all the information you need. Prescriber Information (PI) /labels evolve over time and different PI sheets for different brands of the same generic drug will include information from different studies

Studies available to one National Regulator may not be available to another so check at least 2 major regulators

Venlafaxine data


EMA - EPAR

FDA

Review

Product Label (prescriber Information)

TOXNET

HSDB summary

PUBMED

Published studies from development phase

√

√

√

√

X

X


Step 2 Identify Key Hazards

Pharmacokinetics


Well absorbed orally, plasma half life 5 hrs Volume of Distribution 7.5 L/kg, bioavailability 92%

This data can be used to estimate achieved systemic concentrations from a given exposure

Almost all API is metabolised to ODV and ODV conjugates, and then excreted in the urine Hepatic or renal impairment might increase systemic exposure by

delaying elimination Probably not a substantial concern at low exposures The ODV metabolite is biologically active

Pharmacology


IC50 values for neurotransmitter reuptake (concentration producing a 50% inhibition of target receptors) – a measure of potency – the lower the number the more potent for Noradrenaline is 300 nM For 5-Hydroxy-tryptamine is 50 nM (5-HT is also known as Serotonin )

Need a substantial proportion of the uptake inhibited for some period of time to produce a therapeutic or pharmacological effect

Calculate dose to achieve IC50 assuming 100% bioavalability and instant absorption (ie be conservative) Vd for a 50 kg person is 375 L MW 314 g/M Bioavailability essentially 100%

So, simplistically, 50 nM in body fluids would require a dose of

𝑑𝑜𝑠𝑒 = 50𝑛𝑀 ∗314𝑛𝑔

𝑛𝑀∗ 375𝐿 = 5.9 𝑚𝑔

Realistically absorption is not instantaneous and metabolism and excretion start immediately so achieved levels would be << than calculated and quite transient

Hence therapeutic dose is >> 6 mg (25 mg tid, 75 mg/day as a starting dose) Exposure of < 50% of the IC50 value (3 mg/day or 0.06 mg/kg bw/d) very unlikely to be

pharmacologically active

Clinical efficacy and IC50


Relationship Between Dose, Plasma Level, Potency and Serotonin (5-HT) Uptake

SSRIUsually Effective Dose

(mg/day)Plasma Level† Concentration nM In Vitro Potency IC506 Inhibition of 5-HT Uptake Pump (%)

Citalopram 40 85 ng/ml 260 1.8 60%

Fluoxetine 20 200 ng/ml 660 6.8 80%

Fluvoxamine 150 100 ng/ml 300 3.8 70%

Paroxetine 20 40 ng/ml 130 0.29 80%

Sertraline 50 25 ng/ml 65 0.19 80%

† Plasma level for fluoxetine represents total of fluoxetine plus norfluoxetine given comparable effect of each on 5-HT uptake pump; parent

SSRI alone shown for all others. Also, plasma levels are a total of both enantiomers for citalopram and fluoxetine.

Reference http://www.preskorn.com/books/ssri_s3.html

Clinical efficacy appears to be associated with• blood levels equivalent >100 + fold IC 50 and • inhibition of >60%SO – POD based on IC50 value highly conservative and therefore protectiveBUT – may be too conservative and therefore costly

Carcinogenicity


FDA Product Label – Not a carcinogen No evidence of carcinogenicity in rats or mice at doses equal to or

greater than the maximum Human Recommended dose The PI does not provide a NOAEL for general toxicity but does for

carcinogenicity 120 mg/kg bw/day There is an opportunity to use the comparative blood levels in rats at

120 mg/kg bw/d and humans at 225 mg/person/day to reduce adjustment factors but unlikely to be useful for this drug (because other endpoints will determine the PDE)

Genotoxicity


FDA Product Label venlafaxine not genotoxic

ODV mostly negative results but one study at high exposures relative to human therapeutics (& therefore contamination level) was positive

Weight of evidence indicates not a genotoxin at plausible exposure levels.

Reproduction and development - Fertility


The parent API had no effect but the metabolite reduced fertility in rats at a systemic exposure (AUC) = to 2-3 x the maximum human dose of 225 mg/day The comparison was based on exposure calculated from AUC Rat dose unknown and not readily calculated from this description The comparison is based on a LOAEL, the NOAEL is not given Could use human dose x 2 but then apply AFs to cover cross species extrapolation plus interindividual variation plus lack of NOAEL So

human dose 4.5 mg/kg bw/d x 2 = 9 mg/kg bw/d Very messy

BUT - US Pharmacopeial Convention MSDS indicates no fertility effect from venlafaxine in rats at up to 8 times max human dose (dose ≠AUC) – ie a NOEL NOEL for venlafaxine = 8 x 4.5 mg/kg bw/d = 36 mg/kg bw/day

There is no discordance between these 2 findings. Quite likely the rat required a dose >> 8 times human dose on mg/kg bw/d basis to achieve 2 X the AUC – this is a common finding

Foetal Development


TGA Categorization B2 Drugs which have been taken by only limited number of pregnant women and women of childbearing age, without

an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of foetal damage

Not a teratogen – no malformations ? Foetal survival reduced

But generally related to decreased maternal care resulting from pharmacological effects on the dam.

NOAEL 1.4 x human maximum dose of 225 mg/day Assume per EMA guidance a human bw of 50 kg Then dose in humans = 225÷50 = 4.5 mg/kg bw/day Rat NOAEL is therefore 1.4x4.5 = 6.3 mg/kg bw/day

Need to check post market literature for human experience to add or reduce weight to the other observations (reduced weight gain, stilborn)

Some discordant data


In a perinatal toxicity study in rats after oral dosing of dams with 30 mg/kg or more,

decreased pup survival following birth was observed. This effect is secondary to

treatment decreased maternal care, and is also seen with other antidepressants. (TGA PI)

In a developmental study in rabbits (Sloot et al., 2009) administered venlafaxine HCL at

0, 45, 90 or 135 mg/kg bw/d cardiovascular related malformations were observed

in 12/161 at 135 mg/kg bw/d and 5/161 at 90 mg/kg bw/d. The NOAEL for foetal development in this study appears to be 45 mg/kg bw/d. Skeletal malformations have also been

reported for this study but details are not available

Other rabbit studies apparently negative

Human prospective trial found no teratogenic or survival effect

Venlafaxine late in the 3rd trimester may result in functional and behavioural deficits in the newborn infant including respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia,

hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.

The clinical features are consistent with either a direct toxic effect or drug discontinuation syndrome and, occasionally, may resemble a serotonin syndrome.

The complications may require prolonged hospitalization, respiratory support, and tube feeding (Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk)

What to do


Consider evidence Available human data indicates teratogenic risk is low at worst, Risk of Persistent Pulmonary Hypertension (PPH) from late

pregnancy exposure to therapeutic doses– dose relationship not characterised

Animal data largely negative in the rat, except reduced fertility at 2 X human exposure for the metabolite but we have a NOEL for the parent drug so use that

positive for malformations in at least one rabbit study. Rabbit NOAEL 45 mg/kg bw/d (?).

Strongest data is that in humans and most immediate risk appears to be PPH but need to ensure any PDE covers potential reduced fertility

Rabbit data has a high NOAEL so unlikely to influence PDE

Other Neonatal Effects


These are known human neonatal effects so critical effects in terms of a PDE

Breast feeding


This is important and needs careful consideration Ideally need data on the nature of the effect and the dose required to

produce it Unlikely to be readily available Need information on the levels in milk compared to maternal blood (higher,

lower or similar) Need to consider the mechanism

If pharmacological, which is most likely, then exposures below pharmacologically active levels unlikely to present a risk

Most of this is not available But… these effects occur at therapeutic doses so unlikely at contaminant levels –

need to check this at the end to ensure you are confident that this assumption is likely to remain true

Other Clinical Data


What side effects occurred at the lowest dose either at levels above placebo or not seen in placebo groups

Which of these are potentially serious (ie life threatening or irreversible)

Are any of these likely to be non pharmacological/idiosyncratic

Side effects at the lowest clinical trial dose of 75 mg/day appear to be pharmacological in nature and therefore unlikely to manifest at low exposures Effect Placebo 75 mg/day

Asthenia (lethargy) 3.3 16.9%

Vasodilatation 0 4.5%

Anorexia 2.2 14.6%

Nausea 14.1 32.6%

Insomnia 9.8 22.5%

Anxiety 4.3 11.2

Impotence 0 5.8

Other Clinical Data


No evidence of a strong sensitising potential

Isolated reports of sensitivity is not unusual for any drug/chemical

Cannot protect against random isolated events

First iteration of PDE - TTC


Venlafaxine is not carcinogenic or genotoxic so a Threshold of Toxicological Concern (TTC) approach would give a PDE of 1.5 µg/kg bw/day – 75 µg /person/day

Need to check that calculations from appropriate animal studies do not yield a lower value

Second Iteration PDE - Pharmacological


Based on the Volume of distribution of venlafaxine and the dose required to yield 50% of the IC50 for neurotransmitter reuptake if administered iv, the minimum anticipated biological effect level (MABEL) would be >> 3 mg/day as calculated earlier

Use 3 mg/day, 0.06 mg/kg bw/day as a NOEL

Calculate PDE

F1: between 2 and 12 for extrapolation between species X

F2: 10 to account for variability between individuals √

F3: 10 to account for repeat-dose toxicity studies of short duration, < than 4-weeks X

F4: 1-10 for severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity X

F5: 1-10 if no NOEL & only an LOEL is available, depending on the severity of the toxicity. X

Apply adjustment factors (F1 -5)

10 for inter-individual variation (F2)

PDE = 3÷10 = 0.3 mg/day

Third iteration – Pharmacological –Minimum daily dose


Minimum daily therapeutic dose is 75 mg

This is a LOEL

Associated with side effects in clinical trials

? Relationship to neonatal effects at this dose

So need uncertainty factors for inter-individual variation and LOEL in place of NOEL

We’ll use 10 x 10

Calculate PDE

75/100 = 0.75 mg/day

Fourth Iteration – Toxicology and Adverse Effects


Critical effects Foetal survival – NOAEL 6.3 mg/kg bw/d Rabbit developmental study 45 mg/kg bw/d (?)

Calculate PDE Select POD - Use 6.3 mg/kg bw/d for foetal survival

Could start with the LOAEL for reduced fertility but the additional UF will yield approx the same value

Identify uncertainty factors F1 – 5 for rats to humans F2 – 10 for inter-individual variation F3 – 1 data includes life time studies F4 – 5, foetal death is a severe irreversible effect F5 – 1 we are using a NOAEL

Total UF = 250 PDE = (6.3 mg/kg bw/day * 50 kg/person)÷ 250 = 1.26 mg/person /day

Compare available PDEs


TTC Pharmacology -Receptor data

Pharmacology -Minimum Dose

Toxicology

Critical Effect Not mutagenic or carcinogenic

IC50 for neurotransmitter uptake, primary pharmacological mechanism

Minimum therapeutic dose of 75 mg/ day (25 mg tid)May be associated with neonatal effects

Reduced fertility in adult rats and foetal death, Rabbit development ?

Uncertainties Highly conservative (low)

Inter-individual variation Inter-individual variation, an effect (therapeutic ) dose

Rat to man, inter-individual, serious irreversible effect

Uncertainty Factor applied

Not applicable 10 100 (10 x 10) 250 (5 x 10 x 5)

PDE (/person/day)

75 µg 300 µg 750 µg 1260 µg

Comment Sets a lower bound Highly conservative assumptions

Simple, useful , calculation but need to check for other end points that may give lower values.tid dosing complicates the PK

Human clinical data takes precedence

Which to use ?• 300 µg/person/day is protective of toxicological endpoints and unlikely to be pharmacologically active• Should be protective of all normal subpopulations and avoids possible Cmax effects• ? Need to consider the follow on/receiving products to ensure there are not other issues that could impinge on PDE

selection

1 . S E L E C T A P P R O P R I A T E N O A E L O R P O D

2 . P L U G I N T O F O R M U L A

3 . D E T E R M I N E U F S

4 . C A L C U L A T E O E L


Worker Exposure Limits OEL

Calculate the OEL


𝑂𝐸𝐿 =𝑃𝑂𝐷

𝑚𝑔𝑑𝑎𝑦

(𝑈𝐹)(𝑆𝑆)(𝛼)(𝑣𝑜𝑙)

Where:POD = Point of Departure in dose per person per dayUF = combined uncertainty factorsSS = factor based on half life of the compoundα = bioavailability factor to convert from oral to inhalational bioavailabilityVol = volume of air breathed in a shift of work = 10 m3

Considerations for Venlafaxine OEL -1 -Pharmacological


POD is 300 µg/person per day based on a pharmacological end point and a body weight of 50kg as stipulated by EMA - however for occupational risk assessment 70 kg is used SO POD becomes 70/50 x 0.3 mg/d = 0.42 mg/d

Uncertainty and other adjustment factors F1: extrapolation between species

Data is in humans or for human receptors so no cross species adjustment

F2: variability between individuals Derivation is already based on conservative assumptions so x 5 is adequate

F3: account for repeat-dose toxicity studies of short duration, < than 4-weeks We have at least summaries for all relevant toxicological endpoints so not needed

F4: for severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity End POD based on reversible pharmacological end point so not required

F5: if no NOEL & only an LOEL is available, depending on the severity of the toxicity. POD is based on a no effect level so not required

Half life is short so SS is 1 ie does not bio-accumulate and is quickly excreted

Oral bioavailability is high so α = 1 no need to adjust for a (potentially) greater absorption from lungs so

SO All adjustment factors combined = 5

Calculate OEL 1


𝑂𝐸𝐿 =0.42𝑚𝑔/𝑑

5𝑥10= 8 µg m-3

What if this is unachievable ?• Revisit each assumption and see if better, more accurate data is available• Consider if exposure is uniform across the working day – ie is exposure 2

hours not 8 & therefore the air breathed factor can be reduced• Can additional PPE be used during the high exposure period• Is the POD for cross contamination the appropriate one for occupational

exposure – eg if POD for PDE is based on a long term study or third trimester effects on the foetus is that applicable to your workforce ?

Calculate OEL 2 – Lowest Human Dose


OEL does not necessarily need to use the same POD as that for the PDE because the exposed population is different

Lowest human dose is 75 mg/kg bw/d Associated with only mild clinical side effects but need to consider possible reproductive effects Women in third trimester of pregnancy - ? working in pharmaceutical manufacture ? Uncertainty and other adjustment factors

F1: extrapolation between species Data is in humans

F2: variability between individuals x 5 Assuming women in late pregnancy not working with this material Children and geriatrics unlikely to be occupationally exposed

F3: account for repeat-dose toxicity studies of short duration, < than 4-weeks We have at least summaries for all relevant toxicological endpoints so not needed

F4: for severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity POD based on reversible pharmacological effects – not required

F5: if no NOEL & only an LOEL is available, Based on a LOEL that is therapeutically sufficient for some patients x 10

Half life is short so SS is 1 ie does not bio-accumulate and is quickly excreted

Oral bioavailability is high so α = 1 no need to adjust for a (potentially) greater absorption from lungs so

SO All adjustment factors combined = 5

Calculate OEL 2


𝑂𝐸𝐿 =75𝑚𝑔/𝑑

10𝑥5𝑥10= 150 µg m-3

Which to use1. Occupationally exposed population unlikely to include the most

vulnerable1. The severely debilitated, 2. Elderly3. Neonates4. Women in late pregnancy (? Breast feeding may be an issue)

2. Use of a less conservative POD is reasonable in the absence of clear evidence of serious adverse effects

3. Side effects at the lowest therapeutic dose are mild4. Continuous exposure throughout a working day at the OEL = 1.5

mg/person -

N O W Y O U H A V E A P D E W H A T W I L L Y O U D O W I T H I T

BartCrofts Scientific Services Pty Ltd; [email protected]

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Exposure Assessment

Over to You


The PDE is specific to an API and transferrable across manufacturing facilities

The Exposure assessment is specific to A specific manufacturing facility

Specific product manufacturing sequence

Specific to a cleaning protocol

So You can outsource or purchase the PDE determination

But the exposure assessment will require some in house consideration unless you want to have each production sequence risk assessed

Exposure Assessment

Exposure The amount of a substance an organism is exposed to through

ingestion, inhalation, or dermal application, etc.

Depending on context it may also be the Plasma or tissue concentration of a substance (esp for drugs)

Exposure in hazard characterisation Dose, route, frequency, duration

Plasma or tissue concentration

Exposure in the prospective human population ?? Source, route, magnitude (intake, absorption), duration

Specific populations: children, occupational exposure, general population

Plasma concentration (biological monitoring)


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Exposure

The actual systemic exposure to a substance depends on the dose, absorption, clearance (elimination) and, for exposure of a particular tissue, tissue distribution

Plasma substance concentration is the best and most reliable determinant of systemic exposure

After oral ingestion exposure may vary & be different for Areas of the GIT Systemic sites Organs of excretion

Kidney Liver Gall bladder Urinary bladder


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Determinants of exposure to a contaminating API


Quantity of API from donating product residual in equipment after clean up, or potentially mobile to follow on products

Size/volume of follow on product Both batch size and dose form size

Determines amount of contaminating API per unit dose

Eg large or small tablet Paracetamol (4 grams active per day) versus digoxin or thyroxine (100 µg/day)

Large or small volume injection Insulin versus normal saline for infusion

Frequency of administration of follow on product How many times a day ? Course of treatment – prn, a course of a week

WHO is exposed All ages and both sexes or just geriatrics, children, men only etc

May impact selection of PDE If a specific population sensitive to a critical effect that determined the PDE is not

treated with the follow-on product than a higher PDE may be available

Steps to Assess Exposure


1. Measure or estimate the maximum amount of API that could be residual on a piece of equipment or be introduced into a follow on product by whatever means

Residual material in equipment or cleaning materials Dust – ambient, fallout from surfaces, dust extractors etc Clothing of workers ????

2. For each potential follow on product estimate Maximum Amount of contaminating API per batch of follow on product Maximum amount of API contaminant per unit dose of follow on

product Maximum number of dose units per person for the most sensitive patient

sub population (children, pregnant women, patients in renal failure etc)

3. Compare theoretical maximum intake with appropriate PDE4. Determine risk management requirements

Highest risk


A low potency, high dose volume, high frequency product following on from a high potency low dose volume product

A small percentage contamination will lead to a larger exposure to contaminant because the amount of contaminated product taken is higher

Eg high potency long half life drug taken once a day as a very small tablet followed by a low potency drug in a large table taken 4 hourly


Risk Management

Extreme

High

Moderate

Low

Negligible

Nature and Severity of Effects

Potency (Min. dose) mg/dayOr PDE µg/person/day

mild, not acute, reversible

mild acute reversible

moderate not acute reversible

moderate acute reversible

severe not acute reversible

severe acute reversible

severe irreversible

Very High <0.1

High 1-10

Moderate 10-100

Low >100

Identifying High Risk APIs for Contamination ControlRisk Banding

Example of a possible in house risk banding approach to classification of API risk

ISPE 4 band System for Performance based OELs


Category I > 100 µg/m³

Low to moderate toxicity,

no teratogens, mutagens, or carcinogens,

low acute/chronic systemic effects,

reversible effects,

first aid/simple medical treatment.

local exhaust and general ventilation

adhering to normal cGMPs usually sufficient

hair and shoe covers and the requirement to change into a uniform that is laundered or replaced. For process areas, access to change/locker rooms and showers is required.

Category II 100 µg/m³ - > 20 µg/m³

Irritant;

good exposure warning properties,

no teratogens, mutagens, or carcinogens,

onset of symptoms is immediate,

low acute/chronic systemic effects, reversible effects,

requires first aid/simple medical treatment.

requires the use of special equipment such as unidirectional laminar flow booths to create an additional separation between the operator and the materials being handled.

Process areas must have adjoining change/locker rooms available.

ISPE Categories


Category III 20 µg/m³ - > 5 µg/m³

Moderate to high acute systemic toxicity, moderate chronic systemic toxicity,

reversible effects, sensitizer,

onset of symptoms immediate to delayed,

weak mutagens,

moderate degree of medical intervention may be required,

compounds of unknown toxicity. –

another level of control (barrier technology) must be used to separate the operator from the material being handled.

Process areas must have adjoining change/locker rooms, and a decontamination area is strongly recommended.

Category IV <5 µg/m³

Highly potent, high acute and/or chronic systemic effects,

irreversible effects,

extreme sensitizer, mutagen, developmental toxicity, reproductive toxicity or carcinogen,

none or poor warning properties,

immediate and delayed onset of symptoms,

high degree of medical intervention needed.

to meet the containment requirements, Isolation Technology such as robotics, or glove boxes with Rapid Transfer Ports (RTPs) need to be used.

Process areas must have adjoining change/locker rooms for production, maintenance, service, and decontamination. Decontamination required prior to entry to change/degowning room.

Risk Management Options


A facility by facility consideration, for example.

Extreme Risk (eg micro dose genotoxin, teratogen, allergen,)

Dedicated, or highly product limited, facility or production line Enhanced and routinely QC/QA monitored cleaning protocols

High (eg low dose, allergen with moderate threshold, non genotoxic acute systemic toxicity, irreversible toxicity, teratogen, neurotoxin) Limited, pre designated production sequences Enhanced and QC/QA monitored cleaning protocols

Moderate (low dose, reversible but moderate acute systemic effects)

Broader pre-designated production sequences Some specific sequence constraints or exclusions Cleaning protocol validation plan

Very Low (low potency, low hazard, )

Largely unconstrained production sequences Routine cleaning validation

Negligible (low potency, low hazard, - low toxicity vitamins, food like supplements, antacids)

Unconstrained production sequences Routine cleaning validation

Unacceptable risk

Negligible risk

Acceptable Risk

Regulatory/Legal

Socio-Political

Practical

Commercial

Economic

Ethical

Potential for harm

Cost/Benefits

Factors Influencing ‘Acceptable’ Risk


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