extractables & leachables - testo industrial...

EXTRACTABLES & LEACHABLESThe AssessmentThe Assessment

How to organize Extractables Assessments? Considerations from Pharmaceutical Production up to finished Drug Container

Dr. Andreas Nixdorf

I should like to take this opportunity to pay due tribute to Thomas Egert (Boehringer Ingelheim) for f i l di i d hi t ib timany professional discussions and his contributions.

SGS Life Science Services 2014SGS Life Science Services 2014

HOW E&L BECAME AN ISSUE, OR:HOW E&L BECAME AN ISSUE, OR:

How did the importance of various leachables/extractablescame to the attention of the FDA?

Reports of PNAs/nitrosamines in elastomers/metered dose inhalers (MDI) Vulcanization accelerators/2-Mercaptobenzothiazole in elastomersVulcanization accelerators/2 Mercaptobenzothiazole in elastomers Bisphenol A in PU Other classes of L/Es (e. g. metal container residues affecting drug products

safety) E&Ly)

Supply chain not under control E&L Evolutionary Process

late 80‘s

Process …

Leachables in Metered Dose

~ late 80 s

2

Leachables in Metered Dose Inhaler Drug Products

E & L DEFINITIONS

Extractables are . . . chemical compounds that are forcibly. . . chemical compounds, that are forcibly

removed from drug product container closure systems, packaging, or from devices under i l b t ditirigorous laboratory conditions.

. . . potential / tentative leachables

What is inside . . . . . . may come out !!!

Leachables areLeachables are . . . chemical compounds that migrate from drug product

container closure systems, packaging, or from d i d l / bilidevices under normal use/stability.

may present a potential safety risk generally subsets of extractables

3

generally subsets of extractables

3

APPROVAL OF A CONTAINER CLOSURE SYSTEM

Description

- IN WHAT AUTHORITIES ARE INTERESTED IN -

Description

SuitabilityDevice /

ProtectionSafety Extractables & l

Packaging

yLeachables

CompatibilityFunctionrip

tion

abili

ty

Con

tro

bilit

yFunction

Quality ControlDes

c

Suita

Qua

lity

Stab

Stability

Q

4

4

Compatibility / ProtectionCompatibility

Ad ti

Protection

E t li ht d Adsorption Degradation Change of pH

Exposure to light andtemperature

Loss of solvent Precipitation Discoloration Leachables

Exposure to reactive gases Adsorption of water vapor Microbiological conterminationg

Suitability for usePerformance Functionality Drug delivery

SafetyDrug delivery

The product does have an adverse effect on the packaging.

5

g gThe pack packaging does have an adverse effect on the product.

FDA’S DEGREE OF CONCERN

Likelihood of Packaging Component-Dosage Form InteractionDegree of Concern Associated with

the Route of Administration Non-solid dosage form: High Solid dosage form (Powders):

Medium

Solid dosage form:

Low

Highest Inhalation Aerosols / Solutions; Inhalation Powders

Injections / Injectable Suspensions

Sterile Powders / Powders for

Injection;

High Nasal Aerosols / SpraysHigh Nasal Aerosols / Sprays

Ophthalmic Solutions /

Suspensions

Transdermal

Ointments / PatchesOintments / Patches

Low Topical Solutions / Suspensions;

Topical / Lingual

Aerosols;

Topical Powders;

Oral powders

Oral Tablets / Oral

(Hard and Soft Gelatin) Capsules

Oral Solutions / Suspensions

6

Source: FDA Container Closure Guidance …

EMA’S PERSPECTIVE ON DEGREE OF CONCERN

Plastic packaging material for drug products forPlastic packaging material for drug products for

oral and topical other than ophthalmic administration inhalation, parenteral and ophthalmic administration

Non-solid dosage formsSolid dosage form Non-solid dosage formsSolid dosage form

yes no

Material described in Ph.Eur. or in thepharmacopoeia of a Member State and/orin accordance with Foodstuff legislation

yes no

Material described in Ph.Eur. or in thepharmacopoeia of a Member State

• General information • General information• Interaction studies

• General information incl. composition

• Extraction studies

y

• General information• Interaction studies

if necessary

• General information incl. composition acc. to EP

• General information incl. composition

• Extraction studies • Interaction studies • Toxicological

information

• Interaction studies • Interaction studies • Toxicological

informationincl. migration(leachables) studies

7

Source: EMEA Guideline on plastic immediate packaging materials, 19 May 2005 (CPMP/QWP/4359/03)7

QUALITY BY DESIGN (QbD) – THE GOALQUALITY BY DESIGN (QbD) THE GOALIn a Quality by Design system: The product is designed to meet patient needs and performance requirementsThe product is designed to meet patient needs and performance requirements The process is designed to consistently meet product critical quality attributes The impact of starting raw materials and process parameters on product quality is

understood The process is evaluated and updated to allow for consistent quality over time Critical sources of process variability are identified and controlled Appropriate control strategies are developed Appropriate control strategies are developed

What must be considered in E&L strategies? Understand how process parameters affect CQA (Critical Quality Attributes) Conduct risk analysis/assessment to:

Identify significant process parameters and raw materials attributes Identify significant process parameters and raw materials attributes Develop risk mitigation strategies Establish appropriate control strategy to minimize effects of variability on CQAs M f t i i d d t/ t i l k l d d h i l h i l

8

Manufacturing experience and product/material knowledge and physical-chemical knowledge

WHY STUDY EXTRACTABLES?WHY STUDY EXTRACTABLES?Safety assessment / Qualification E l ti f f t fil t h h f d l t f h ti l d t Evaluation of safety profiles at each phase of development of a pharmaceutical product

For qualification of Container Closure Systems (container selection)

Safety aspects in drug production process (leachables from consumables/single used y p g p p ( gsystems)

Profile presence of toxic substances By correlating extractables to leachables, then determining extractable limits that can provide safetyBy correlating extractables to leachables, then determining extractable limits that can provide safety

aspects on leachables

Change management

Change of packaging material or component of package

Changes of production consumables / equipment / in production conditions

Change of formulation Change of formulation

Change of composition of packaging material

Change of manufacturing process of packaging material

9

Before start do your risk assessment, demonstrate that everything is under control

COMBINATION PRODUCT DEVELOPMENT PROGRESSION (OINDP)

Mid LateEarly Mid Late

Dosage Form LeachablesProof of Concept

Label Claims

Dose selection

Dose/Regimen

FormulationSelection

g

Feasibility Preclinical Phase IIPhase I Phase III Phase IV

Concept Development Safety/Efficacy Efficacy CommercializeManufacturing

MarketedProductManufacturing Product

Packaging

DeviceRoutine ExtractionContr.Extr.Qualification

Qualification Contr. Extr. Routine ExtractionProductDefinition

CommercialManufacturingRequirements

CustomerRequirem.

Met

Design Requirements

Met

DesignCandidate

q

Stage 1 Stage 2 Stage 4Stage 3 Stage5 Stage 6

10

ConceptDevelop.

DesignDevelop.

DesignVerification

DesignValidation

DesignTransfer

Commercialization

SOURCES POLYMER CHEMISTRYSOURCES – POLYMER CHEMISTRYSupply chain not under control?

11

Implications on Quality Throughout the Supply Chain

Patient

IngredientSupplier

Material Supplier

Converter/Assembler PHARM PatientSupplier

MonomersAdditives

SupplierPolymer, Metal

Elastomer

AssemblerMoulder, Device-Packaging MFR

MFR

N-3 ControlN-2 N-1

Extractable Leachable

N 3 ControlN 2 N 1

Certification/Compliance:• Food Contact TestingFood Contact Testing• Pharmacopoeial Testing• Biocompatibility Testing• Extractables Testing (Supplier + Pharm Mfr)

LeachablesTesting

Points of Concern:• Supplier GMP• Change Notification Systems• Quality Agreements / Confidentiality

1212

• Quality Agreements / Confidentiality• Information Exchange !

HOW TO KEEP THE SUPPLY CHAIN UND CONTROL?

THE CHALLENGES THE SOLUTIONSTHE CHALLENGES

Often modifications of polymers

THE SOLUTIONS

Stipulate the obligation gettingp yby vendors.

Permanent changing polymer

Stipulate the obligation getting informed in timely manner by quality agreements.

Qualify alternative vendors; this Permanent changing polymer market.

Qualify alternative vendors; this secures the user the required delivery.

Routinely control incoming

Make certain that your supplier

out e y co t o co gvendors material by chemical profiling critical polymeric components.

Make certain that your supplier keep the quality of his product under control.

Frequently perform quality audits.

13

E&L Consortia by 2014 - An Overview?Industry,

USP, Academia

PQRI

E&L OINDP

OINDPMaterials

Supplier GMP

Single Used Systems

…E&L PODP…

BPSA Bio-Process Systems AllianceE&L Extractables & LeachablesELSIE Extractables and Leachables Safety Information

PODP Parenteral and Ophthalmic Drug ProductsPQRI Product Quality Research InstituteOINDP Orally Inhaled and Nasal Drug Products

14

ELSIE Extractables and Leachables Safety Information Exchange

FDA U.S. Food and Drug AdministrationIPAC-RS International Pharmaceutical Aerosol Consortium

Regulatory & Science

y gUSP United States Pharmacopeia

MILESTONES OF AN EXTRACTABLE / LEACHABLE ASSESSMENT

PROJECT PREPARATION EXPERIMENTAL PHASEPROJECT PREPARATION EXPERIMENTAL PHASE

MILESTONES

PRELIMINARYWORK

RISK ASSESSMENT

EXTRACTABLE STUDY

METHOD VALIDATIONLEACHABLE

Collect Information e.g. suppliers, chemical compatibility of

Evaluate overall process

E al ate risk (ICH

Execute protocols for extractables testing

Method development and validationp y

materials, food compliance etc.

Rank, prioritize and

Evaluate risk (ICH Q8/Q9/Q10/Q11 tools)

Select materials

Identify extractables

Evaluate results

Product specific validation

Leachable studybracket different materials

Execute CDA and contract

Select materials

Study overall project protocol

Generate report

Define specification limits for Leachable

Leachable study

15

contract Define project milestones

study: Toxicological Assessment

MEASUREMENTS FOR EXTRACTABLES AND LEACHBLESLEACHBLES

Extractables Leachables

Qualitative analysis of analyte above an Analytical Evaluation Threshold (AET).

Qualitative analysis looking for the Leachables from product prepared fresh and taken from real-time or accelerated storage

C t ll d t ti t di i diff tg

programs.Controlled extraction studies using different solvents, worst case conditions that maximize/brackets studies outcome.Semi Quantitation of analyte Quantitation of Leachables above a safetySemi-Quantitation of analyte. Quantitation of Leachables above a safety

threshold.

Profiling applying multiple methodsd t t d fit f th t

Tabulation of method used, limits of tifi ti d t i l h tdemonstrated fit for that purposes. quantification and typical chromatograms

validation of methods.Focus on identification, calculation of the amount of extractable/component in the

Identification of unforeseen leached substance above safety limit and routeamount of extractable/component in the

closure device.substance above safety limit and route cause (CAPA).Tabulation of levels of Leachables seen from several batches (3) of product/device.

List of extractables with quantitation, sensitivity of methods and results for

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( )sensitivity of methods, and results for submission.

Extractables and Leachables ProcessExtractables and Leachables Process

Risk analysis on the extractables/leachables process will lead to following conclusions: Inadequate screening of materials will lead to an increased Inadequate screening of materials will lead to an increased

risk for repeating controlled extractables studies with a new material.

The project timeline increase associated with failed material The project timeline increase associated with failed material at the extractables stage will be greater for a device material compared with a simple packaging component.

Inadequate extractables studies will increase the risk of Inadequate extractables studies will increase the risk of failure during leachables qualification (delay 1-3 years !!)

17

Purification Techniques in Down Stream ProzessesPurification Techniques in Down Stream Prozesses

FiltrationPrecipitationLiquid-liquid two-phase separationLiquid liquid two phase separation Chromatography

– Size exclusion (gel filtration)– Ion-exchange– Ion-exchange– Hydrophobic interaction– Reverse- Phase

Hydroxyapatite– Hydroxyapatite– Affinity (protein A,G etc, dyes, metal chelates, lectins etc…)– Fusion proteins (tagging, Fc, Intein, streptavidin etc…)

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THE RISK ICH Q9: SCHEME OF A DOWN STREAM PROCESS

CentrifugeFiltering 1

age

Depth Filtration

Collection

Chromatography 1

Column 1 Sto

ra

Fermentation

Harvest Steps Purification

Virial Inactivation

Filtering 2

Chromatography 2

Filtering 3

Chromatography 3

Filtering 4

Chromatography 4

tora

ge

Sto

rage

tora

ge

Column 2

Purification

Column 3

Purification

Column 4

Purification

St S St

Dia

-ltr

atio

n

tora

ge

Filling, Storage (long Term contact)

19

Fil

St

RISK RANKING AND FILTERING (ICH Q9)RISK RANKING AND FILTERING (ICH Q9)

Compare and prioritize risks

How to perform?How to perform?

Requires evaluation of multiple diverse quantitative and qualitative factors for each risk

Involves breaking down a basic risk question into as many components as neededto capture factors involved in the risk

Th f t bi d i t i l l ti i k These factors are combined into a single relative risk score that can then be compared, prioritized and ranked

20ICH Q9

RISK RANKING AND FILTERING (ICH Q9) EXAMPLERISK RANKING AND FILTERING (ICH Q9)

E l ti f d t d ith i lit

EXAMPLE

Evaluation of products and processes with recurring quality relevant problems

Risk assessment: Risk identification, rationale Process step: the more the process advances towards the end, the

l h ifi i ld d h l h dil iless the purification process could operate and the less the dilution factor applies. It is the opposite as the concentration increases.

Product contact : with operations that change the product quality (microbiology, filtration, virus removal, etc.), the contact surface has more impact on product than simple transfer.

Intermediate storage: during storage, interaction between product and consumable has a high significance (longer contact time).

Process impact / conditions of use : sanitization process (for example: steam or treatment with harsh solvents) is aggressive for

21

the consumable and could increase extractables release

EXAMPLE

RISK RANKING AND FILTERING (ICH Q9)E l ti f d t d ith i lit l t

EXAMPLE

Evaluation of products and processes with recurring quality relevant problems

Risk assessment: Risk evaluationThree columns

based on a g

20 125 > 500

based on a classical approach by multiplying factors

10 400100

Rat

ing

Probability 200251

250505

Tota

l RProbability1: no quality events expected2: could lead to quality events3 C iti l lit t

1 2 3

200251

P b bilit

T

22

3. Critical quality events Probability

RISK RANKING AND FILTERING (ICH Q9) EXAMPLERISK RANKING AND FILTERING (ICH Q9) EXAMPLE

Process Step

Rating Criteriag

1 At beginning of process Size exclusion

5 In middle of process Filtering basic or acidic substances, ion-exchange

10 End of process Filtering of particles

20 Final step ---

Product Contact

Rating Criteria

1 Short term contact, no change of the product quality Small contact surface of filter

5 Long term contact, change of the product quality Large contact surface of filter

20 Intermediate Storage ---

Process Impact / Condition of use

Rating Criteria

1 Solvent with low extraction power for additives Low Temperature

23

5 Solvent with high extraction power for additives High Temperature

RISK RANKING AND FILTERING EXAMPLERISK RANKING AND FILTERING EXAMPLE

For each element, a weighing of critical points will b attributed. The total rating can then be calculated:

Risk evaluation added to production problems:

T t l ti P St P d t C t t P I tTotal rating = Process Step x Product Contact x Process Impact

24

EXAMPLE

RISK RANKING AND FILTERING (ICH Q9)Weighing grid for other plastic consumables risk analysis

EXAMPLE

Total Rating Criticality of the element

1

5

Non critical element

10

20

25

Risk Matrix (1)25

50

100

125125

200

250

Critical element : extractables and leachables studies must be performed / available

400

500

1000

25

2000

EXAMPLE

MeasureRISK RANKING AND FILTERING (ICH Q9)

EXAMPLE

Measure

Ri k

Risk Matrix (2)

CA B HIGH extensiveRisk Filtering

ONE

catio

n MEDIUM

TWO

Clas

sific LOW

THREE

Risk

C

26

HOW LOW SHOULD WE GO? THRESHOLDSHOW LOW SHOULD WE GO? -THRESHOLDS

• Commission Regulation (EU) No 10/2011 on plastic materials and articles i t d d t i t t t ith f dintended to come into contact with food:

Specific migration limits (SML) in Annex I or a generic SML of 60 mg/kg

Overall migration limits of 10 mg of total constituents per dm2 of contact surface

• US 21 CFR Food additives threshold of 1 5 µg/day• US 21 CFR Food additives threshold of 1.5 µg/day

• EMEA guideline on the limits of gentox impurities: threshold of tox. concern 1.5 µg/person/day1.5 µg/person/day

• ICH Q3C EP 5.4, USP <467> for residual solvents

• EMEA guidline on specification limits for residues metal catalysts or metal• EMEA guidline on specification limits for residues metal catalysts or metal reagents

• PQRI Recomondations “Safety Thresholds for Extractables&leachables in

27

yOINDP and PODP”

SAFETY CONCERN THRESHOLD (SCT) FOR OINDP

The threshold below which a leachable would have a dose so low as to t li ibl f t f i i d i ipresent negligible safety concerns from carcinogenic and non carcinogenic

effects.

• Based on Total Daily Intake (TDI) and indepent of doseBased on Total Daily Intake (TDI) and indepent of dose

• Assumees one in a million risk of cancerous effect

• Uses 50 kg human weight (vs 70 kg)• Uses 50 kg human weight (vs. 70 kg)

PQRI proposes a SCT of 0.15 µg per day for an individual leachable in an OINDPOINDP

Be considered qualified, thus no tox assessment would be required.

Expect: PAH´s Nitrosamines 2-Mercaptobenzothiazole Expect: PAH s, Nitrosamines, 2-Mercaptobenzothiazole

A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer

28

causing cancer.

QUALIFICATION THRESHOLD (QT) FOR OINDPQUALIFICATION THRESHOLD (QT) FOR OINDP

The threshold below which a given non-carcinogenic leachable is not id d f f t lifi ti (t t) l th l h blconsidered for safety qualification (tox assessment) unless the leachables

presents structure-activity relationship (SAR) concerns

• The structure–activity relationship (SAR) is the relationship between theThe structure activity relationship (SAR) is the relationship between the chemical or 3D structure of a molecule and its biological activity

• PQRI proposes a QT of 5 µg per day for an individual leachable in an p p µg p yOINDP

29

THRESHOLD OF TOXICOLOGICAL CONCERN (TTC) FOR PODP

Developed to define a common exposure level for any unstudied chemical th t ill t i k f i ifi t i i it th t i ff tthat will not pose a risk of significant carcinogenicity or other toxic effects

• Acceptable limit for genotoxic impurities in drug substances

• Corresponding to a 10-5 lifetime risk of cancer

• Uses 50 kg human weight (vs. 70 kg)

TTC of 1.5 µg per day for an individual leachable

Higher limits may be justified under certain conditions such as short-term i dexposure periods

In genetics, genotoxicity describes the property of chemical agents that damages the genetic information within a cell causing mutations, which may lead to cancer

30

g g , y

QUANTITATIVE EVALUATION: THE USE OF SAFETY THRESHOLDS

Correlating Threshold Values for Different levels of Cancer Risk

ent/d

ay)

1 5 *ke(µ

g/pa

tie

*FDA

0.15

1.5 *

*

daily

inta

k *EMEA-TTC

PQRI

-6 -5 -4 -3 -20.00015 *To

tally

Log (lifetime cancer risk = LCR)Decreasing risk Increasing risk

31

Norwood, D.L. and Ball, D. Product Quality Research Institute: Safety thresholds and best practices for extractables and leachables in orally inhaled nasal drug products, PQRI submission 2006.

THE USE OF SAFETY THRESHOLD –ANALYTICAL SENSITIVITY

Threshold concepts that have been developed for safety qualification of leachables in OINPD can be extrapolated for the evaluation and safety qualification of leachables infor the evaluation and safety qualification of leachables in any Parenteral and Ophthalmic Drug Product

Consideration includes factors and parameters such as dose, daily intake, and Safety Concern Threshold (SCT) = 0.15 µg/Day

These concepts are described by the PQRI working group: These concepts are described by the PQRI working group: www.pqri.org

Safety Thresholds and Best Practice for Extractables and Leachables in Orally Inhaled and Nasal Drug Products (OINPD), PQRI (2006)

32

THE USE OF SAFETY THRESHOLD - HOW LOW IS “LOW”?

ANALYTICAL EVALUATION THRESHOLD (AET) Extractable studies should be guided by an AET

Based on an accepted safety evaluation threshold or SCT

At the AET value or above, a chemist should begin to identify a particular leachable and extractable and reportidentify a particular leachable and extractable and report for potential toxicological assessment

Advantage of an AET Advantage of an AET The sensitivity for leachable and extractable methods can be

postulated

33

THE USE OF SAFETY THRESHOLD - HOW LOW IS “LOW”? EXAMPLE

ESTIMATING AET Example :

5 d d 5 doses per day 200 doses per canister 0.1g component (material/container)

Estimate AET: Convert SCT (0.15 µg TDI) to µg/canister

– 0.15 µg/day x 200 doses/canister = 6.0 µg/canister0.15 µg/day x 200 doses/canister 6.0 µg/canister 5 doses/Day

– 6.0 µg/canister = 60 µg/g 0.1g component

The response of a final AET can be based on an appropriate internal standard.

What about analytical uncertainty?

34

What about analytical uncertainty?

The Use of Safety Threshold -HOW LOW IS EXAMPLE

“LOW”?

ESTIMATING AET & ANALYTICAL UNCERTAINTY The PQRI working Group recommends:

The estimated AET be defined as %RSD in an appropriately constituted response factor dada base

Or A factor of 50% of the estimated AET. In fact uncertainties ranges from 15% - 80%

Final AET = Estimated AET x (1 – analytical uncertainty) Analytical uncertainty = Max (%RSD or 0 5) Analytical uncertainty Max (%RSD or 0.5) Example: Final AET for Extractables 30 µg/g = 30 ppm

35

THE USE OF SAFETY THRESHOLD – AET E&LTHE USE OF SAFETY THRESHOLD – AET E&LEXAMPLE

AET line(Leachables)( eac ab es)

Final AET line

50% offset

Internal Standard: Irganox 1035 at Final -AET of 30 ppm

Final AET line(Extractables)

36

Internal Standard: Irganox 1035 at Final AET of 30 ppm

CONSIDER STRESSING PROCESS CONDITIONSCONSIDER STRESSING PROCESS CONDITIONS

Carbonic acids:C1, C2, C3 etc.

C C Ald h dGamma 20-25, 45 kGy

C2 – C5 -Aldehydes

Ketones

, y

BHT derived from Irganox 1010, 1076

2 5 di t t b t l b d 2 5 2,5-di-tert-butyl benzene and 2,5-di-tert- butyl phenol from Irgafos 168

37

BHT: 3,5-di-tert-butyl-4-hydroxytoluol

ANALYTICAL CHALLENGES OF EXTRACTABLES PROFILING

THE CHALLENGES

A l t d d t h i t

THE SOLUTIONS

U d t d l h i t Analyte dependant on chemistry of container closure system

Understand polymer chemistry

Analyte concentration depends on extraction conditions

Choose realistic extraction conditions and appropriate tools for analyte enrichment

Analyte are complex mixture of chemicals

Choose appropriate tools for Analytes are present at trace

levels and should be identified above the analytical evaluation

Choose appropriate tools for separation and detection

38

ythreshold (AET)

CHOOSE REALISTIC EXTRACTION CONDITIONS

A complete extractables assessment will involve: Multiple extraction

conditions Duration and temperature of p

extraction Material weight to extraction

matrix volume Extraction process

More aggressive conditions than the whichconditions than the which system will normally be used

39

CHOOSE REALISTIC EXTRACTION CONDITIONS – SOLVENTS

Select 3-4 solvents which brackets the real use conditions!

Soft solvents: Water at neutral pH (AD, ADIP, NAD) Extraction Water at high pH (9.5) and low pH (2.5) (AD) Extraction

below boiling point Drug vehicle if feasible (AD) Extraction below boiling point Mixtures composed of aqueous (buffer) and organic modifier:

isopropyl alcohol/water (1:1 mix)(AD, ADIP, NAD) Extraction below boiling point( , , ) g p

Harsh solvents are Extraction : Dichloromethane or MTBE n-Hexane Isopropyl alcohol Dichloromethane or MTBE, n Hexane, Isopropyl alcohol

(ADIP, NAD) Isopropyl alcohol (AD) AD: aqueous drugs

ADIP: AD involving organic propellants

40

g g p pNAD: non-aqueous drugs

CHOOSE REALISTIC EXTRACTION CONDITIONS – ANALYTICAL TOOLS

Extraction• Soxhlet extractors, reflux extraction• Avoid Microwave oven extractionAvoid Microwave oven extraction• Avoid Ultrasound-assisted extraction• Avoid Accelerated Solvent Extraction (ASE)

Cleanup Procedures and Sample Enrichment• Liquid-phase extraction• Solid phase e traction• Solid-phase extraction• Precipitation of dissolved polymer• Analyte concentration by evaporation of solvent• Solvent switching to be compatible to analytical technique

41

CHOOSE REALISTIC EXTRACTION CONDITIONS – ANALYTICAL SENSITIVITY EXAMPLE

Analytical methods sensitivity• Correlate solvent volume, e.g. sample weight, Analytical

Evaluation Threshold (AET) with Limit of Quantitation of the ( )analytical method to surpass methods sensitivity (LOQ)

f tghtSampleWeigμg/gAETM ][][ factor

mlExVolgp gμg gM S

][][][

AET - the allowable amount/substance to be released representing the AET

MS - the posited methods analytical sensitivity with MS > LOQ

ExVol - the volume of extraction solvent

factor - the concentration factor to adjust methods sensitivity

42

CHOOSE REALISTIC EXTRACTION CONDITIONS: AET CONCEPTS

What do we do with peaks that fall within the region bounded by the AAL and the AET?

Analytical Action Limit

No problem, above the AAL –Line can be identified

Final AET line (Extractables)

43

No problem, less than AET line

CHOOSE APPROPRIATE TOOLS FOR SEPARATION & DETECTION

Volatiles organics by GC: H d t h i TDMS FID d MS d t t

SEPARATION & DETECTION

Head-space technique, TDMS, FID and MS –detector

Semi-Volatiles organics by liquid injection GC: FID and MS detector FID and MS detector

Non-Volatiles organics by HPLC: DAD, LC-MS/(MS) with accurate mass assignments

Metals / Elements: ICP-MS, ICP-OES

Kations, Anions Ion chromatography

S i l T h i f iti l d Special Techniques for critical compounds: GC-TEA for Nitrosamines Perfluorinated Carboxylic acids, -Amides, -Sulfonamides by LC-MS/MS

44

NMR- Technology and others44

CHOOSE APPROPRIATE TOOLS FOR SEPARATION & DETECTION

Identification Categories Establish a classification scheme that characterizes the

significance of peak identification data (tentative, confident,significance of peak identification data (tentative, confident, confirmed and unknown).

Best identification means the comparison of both the retention index and the mass spectrum of an extractedretention index and the mass spectrum of an extracted component with its authentic reference standard

Identification category

Identification Data

A I t t ti f M t t i

Attribute Description

Confirmed A Confirmed identification means that identificationA Interpretation of Mass spectrometric fragmentation behavior or component could be grouped to a series

B Confirmation of molecular weight

C Confirmation of elemental composition (not conducted in this study)

Confirmed A Confirmed identification means that identification categories A, B (or C), and D (or E or F) have been fulfilled.

Confident A Confident identification means that sufficient data to preclude all but the most closely related structures have been obtained, Library match factor ≥ 90.

Tentative A Tentative identification means that data have been y)D Mass spectrum matches automated library or

literature spectrumE chromatographic retention index match

authentic specimenF Mass spectrum and chromatographic retention

index match authentic specimen

obtained that are consistent with a class of molecule only.

unknown No sufficient information’s could be obtained

45

index match authentic specimenX No characterization possible

LEACHABLES STRATEGYLEACHABLES STRATEGY

Validate the analytical methods

Methods for leachables Methods for leachables studies are specific to the finished product

D i h lf lif Determine shelf-life acceptance criteria for leachables based on the t i l i l i k ttoxicological risk assessment

46


Perform stability studies according ICH (accelerated) With the drug product With placebo formulation With placebo formulation With other “inert” primary packaging material containing the

drug product for comparisonCh t iti f th k d d d t Change storage position of the packaged drug product:

47


Storage Conditions and Suggested Points for Leachables Analysis

ConditionTemperature

[°C]Relative Humidity

[%RH]Time Points

[months]25 2 60 5

Long Term1 25 ±2 60 ±50, 6, 12, 24, 36

30 ±2 65 ±5Intermediate 30 ±2 65 ±5 0, 6, 12, 24, 36Intermediate 30 ±2 65 ±5 0, 6, 12, 24, 36Accelerated 40 ±2 75 ±5 0, 3, 6, (9, 12)

1 Either set of conditions can be used for Long Term Storage

48

PODP Safety Assessment Triad

Material Characterization (Controlled Extraction Study);(Controlled Extraction Study);

Screening and SelectionExtractables as tentative leachables

Simulation Study(Simulated Extraction Study)

Worst-Case Safety AssessmentExtractables as probable leachablesExtractables as probable leachables

Migration Study(Target Leachables Study)( g y)

Actual Case Safety AssessmentConfirmed leachables

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Jenke, PQRI PODP WS Bethesda, Feb. 2011


EXTRACTABLES AND LEACHABLES CORRELATION

Establish qualitative correlation between profiles Demonstrate that compounds detected in the leachable

studies were also present in the controlled extractables studies

Demonstrate that levels of leachables obtained from leachables studies are generally less than the levels of extractables obtained in the quantitative controlled extraction studies

Use multiple batches in Extractables and Leachables Studies

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MILESTONES OF AN EXTRACTABLES / LEACHABLES ASSESSMENT – THE LINK

Extract

FINISHED PRODUCT

PACKAGINGMATERIAL

Identify Extractant

Packaging Component

ExtractablesLeachables

DiscoveryId if

Investigate

ExtractablesLeachables

DiscoveryIdentify

InvestigateFinished Product

Determine toxicity of Extractant

FINISHED

IdentifyDetermine Relevance

Develop & Validate

Finished ProductIdentify

Determine Relevance

Develop & Validate

Finished Product

Linking of chemical relashionship

Linking of chemical relationship

Develop method for assaying

extractant in drug product

Assay for presence of leachables.

Validate method

for leachable

Put product

on

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leachable in drug stability

THANK YOU FOR YOUR ATTENTIONTHANK YOU FOR YOUR ATTENTION

LIFE INSPIRED

Dr. Andreas NixdorfTeam Leader E&L/Senior ScientistLife Science ServicesSGS GSGS Germany

phone: +49 6128 744-372 fax +49 6128 744-700 il andreas nixdorf@sgs com e-mail : [email protected]

52

ANNEX – IMPORTANT REGULATORY REQUIREMENTS

Guidelines (1):

EMEA: Guideline on plastic immediate packaging materials. EMEA: Note for guidance on specific limits for residues of metal catalyst.g p y EMEA: Guideline on the limits of genotoxic impurities. ICH Q8: Pharmaceutical development.

ICH Q6A: Specifications: Test procedures and acceptance criteria for new drug ICH Q6A: Specifications: Test procedures and acceptance criteria for new drugsubstances and drug products: chemical substances.

ICH Q3C: Guideline for residual solvents ICH Q3B: Impurities in new drug substances:

Impurities arising from excipients present in a new drug product or extracted or leached from the container closure system are not covered by this guidance.

Directive 2003/63/EC amending Directive 2001/83/EC (Medicinal Products for Human Use)

COMMISSION REGULATION (EU) No 10/2011: on plastic materials and articles

53

( )intended to come into contact with food.


Guidelines (2):

US: Container closure systems for packaging human drugs and biologics US: Container closure systems for packaging human drugs and biologics US: CFR 174 – 186 Indirect food additive Regulations Medical devices: ISO 10993: Biological evaluation of medical devices (Parts 1 –

20)20) US: “Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products

– Chemistry, Manufacturing, and Controls Documentation” (FDA-Guidance for I d t )Industry)

US: “Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products” –Chemistry, Manufacturing, and Controls Documentation” (FDA-Guidance for I d t )Industry)

54


Compendium Testing (3):

Ph. Eur. 3.1. Materials used for the manufacture of containers- Monographs for selected polymers

Ph. Eur. 3.2 Containers- Monographs for different types of containers

USP: Chemical / Physical Tests:<381> Elastomeric Closures for Injections<661> Containers (will be changed soon)

USP Biological Tests USP Biological Tests<87> Biological Reactivity Tests, In Vitro (Cytotoxicity tests)<88> Biological Reactivity Testing, In Vivo (Class Tests)<1031> Biocompatibility<1031> Biocompatibility

55


Compendium Testing; revision of USP in progress (4):

USP <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems

USP <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging Delivery Systems

USP <1664 1> Orally Inhaled and Nasal Drug Products USP <1664.1> Orally Inhaled and Nasal Drug Products

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ANNEX LITERATUREANNEX – LITERATURE

Recommended Literature (5): 2006: “PQRI Safety Thresholds and Best Practices for E/L in OINDPs” D J Ball D L Norwood C L M Stults L M Nagao; “ Leachables and D. J. Ball, D. L. Norwood, C. L. M. Stults, L. M. Nagao; Leachables and

Extractables Handbook”; Wiley 2012. Pharmaceutical Research, Vol. 25, No. 4, April 2008 (# 2007) “Best Practices for

Extractables and Leachables in Orally Inhaled and Nasal Drug; Products: AnExtractables and Leachables in Orally Inhaled and Nasal Drug; Products: An Overview of the PQRI Recommendations.”

J. of Liquid Chromatography & Related Technologies; Vol. 27, No. 20 (2004) 3141 3176 “Guideline for the Design Implementation and Interpretation of3141-3176. Guideline for the Design, Implementation, and Interpretation of Validation for Chromatographic Methods used to Quantitate Leachables/Extractables in Pharmaceutical solutions.”Regulatory Toxicology and Pharmacology 44 (2006) 198 211 “A rationale for Regulatory Toxicology and Pharmacology 44 (2006) 198–211 A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity.”

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