leachables and extractables: from regulatory expectations to … · 2019-10-04 · drug product...

Leachables and extractables:

From regulatory expectations to

laboratory assessment6th European Forum on Extractables, Leachables, Medical Devices and

Food Contact Materials Testing

Dr. Martina Ribar Hestericová | Drug Product Services | 26 September 2019

Certain matters discussed in this presentation may constitute forward-looking statements. Thesestatements are based on current expectations and estimates of Lonza Group Ltd, although LonzaGroup Ltd can give no assurance that these expectations and estimates will be achieved. Investors arecautioned that all forward-looking statements involve risks and uncertainty and are qualified in theirentirety. The actual results may differ materially in the future from the forward-looking statementsincluded in this presentation due to various factors. Furthermore, except as otherwise required by law,Lonza Group Ltd disclaims any intention or obligation to update the statements contained in thispresentation.

Pharma & Biotech | Dr. Martina Ribar Hestericová | 26 September 2019 2

Forward-looking statements


Lonza at a Glance

FoundedEmployees

by the end of 2018

Major manufacturingand R&D facilities

worldwideActive patent

families

Sales in 2018 in CHF

Successful audits

Countries with offices / sites

A global leader and trusted supplier in the provision of contract manufacturing and development services for the life sciences


We enable our customers to define their own tailored solution

customized API delivery & product differentiation

drug substance development

drug product manufacturing

drug substance manufacturing

drug product development

• mammalian & microbial expression systems• cell & gene technologies• bioconjugates

• particle engineering• oral dosage form solutions & delivery systems• capsules• parenteral drug products (injections, infusions)

• delivery systems & device integration• liquid & lyophilized dosage forms• parenteral drug products (injections, infusions)

Small molecules

Biologics

• early and advanced chemical intermediates• customized API*, including HPAPI** • payloads for ADCs***

*API – active pharmaceutical ingredient**HPAPI – highly potent active pharmaceutical ingredient***ADC – antibody drug conjugates


Lonza Drug Product Services (DPS)

Lean & Efficient Product Development Strategies - Investigation and Trouble Shooting SupportRegulatory Experience - Industrial Expertise – Scientific Excellence

Discovery Development MarketPharma / Biotech

Value Chain

Formulatability & Molecule Selection

Early-Stage Development & GMP Supplies

Late-Stage Development, DP Process Characterization

& pre-BLA Support

Formulation Optimization & Line-Extension

Development

Basicresearch

Drugdiscovery

Preclinicaltesting

Early Clinical testing

Pivotal Clinical trials

Commercial Production

& Sales

Life-Cycle Management

Clinical LeadSelection

LaunchFirst-Into-Human

Lonza Services


… needs to follow an integrated approach

Successful drug product development

Choice of excipients

Selection of dosage strength

Considering route of administration

Considering preclinical & clinical dose-range

Route of

administration

Patient capability

Patient safety

Device functionality

Container integrity

& sterility

Product quality & stability

Yield, cost of goods

Process design

E & L

• Extractables: compounds that are released from a material into an extraction solution under relevant exaggerated extraction conditions

• Leachables: compounds that are released from a material into drug substance / drug product (DS / DP) under normal storage / use conditions


Definitions

E&L assessment

• Patient safety

• Product safety (no modification of the API and related product quality impact)

• Compliance with HA expectations

• Guarantee that a contact material does not contaminate the DS / DP


Purpose

E&L assessment


Sources of E&L compounds

Images: creative commons licence,

Shutterstock, licensed by Lonza

• US Pharmacopoeia (USP)

• European Pharmacopoeia (EP)

• ISO 10993 Standards (Biocompatibility – medical devices)

• PQRI – Product quality research institute

• BSPA – Bioprocess systems alliance (single-use systems)

• BPOG – Biophorum operations group (single-use systems)

E&L assessmentRegulatory expectations

10Pharma & Biotech | Dr. Martina Ribar Hestericová | 26 September 2019

• 21 CFR Sec. 211.65 (Equipment Construction) / 21 CFR Sec. 211.94 (Drug product

containers and closures)

• FDA Guidance for Industry: Container Closure Systems for Packaging Human Drugs and

Biologics

• CPMP/ QWP/ 4359/ 03: Guideline on Plastic Immediate Packaging Materials, EMEA

• USP <665> “Plastic components and systems used to manufacture pharmaceutical drug

products” (DRAFT)

• USP <1663> “Assessment of extractables associated with pharmaceutical packaging /

delivery systems”

• USP <1664> “Assessment of drug product leachables associated with pharmaceutical

packaging / delivery systems”

• ICH M7 “Assessment and control of DNA reactive (mutagenic) impurities in

pharmaceuticals to limit potential carcinogenic risk”

E&L assessmentRegulations / guidelines


• Food and Drug Administration (FDA) (2016), 21 CFR Sec. 211.65, Equipment

Construction

• Food and Drug Administration (FDA) (2016), 21 CFR Sec. 211.94, Drug

product containers and closures

• Manufacturing equipment or containers and closures “… shall not be reactive,

additive, or absorptive so as to alter the safety, identity, strength, quality, or purity

of the drug … beyond the official or … established requirements.”

• Attributes “reactive” and “additive” concern the phenomenon of leaching

potentially leading to alteration of “safety”, “quality” and “purity”.



Regulations / guidelines

• FDA Guidance for Industry: Container Closure Systems for Packaging Human

Drugs and Biologics

• Provides general principles on submitting information on packaging materials

for NDA / BLA

• Quite generic, explains what to do, but not how to do it

E&L assessment


Regulations / guidelines

• CPMP/ QWP/ 4359/ 03: Guideline on Plastic Immediate Packaging Materials,

EMEA

• Provides guidance on submitting information on packaging materials for marketing

authorization applications

• Quite generic, tells you what to do, but not how to do it

• Differentiation of risk according to following parameters:

• Administration: Inhalation, parenteral, ophthalmic <-> oral and topical

• Dosage form: Non-solid <-> solid

• Material: Not regulated <-> regulated by foodstuff legislation

• High risk materials demand for extraction studies

• Migration studies necessary when extraction studies have resulted in one or more

extractables

E&L assessment


• USP <665> “Plastic components and systems used to manufacture

pharmaceutical drug products” (DRAFT; formerly <663.1>)

• Applicable to single and multi-use manufacturing systems used during (bio)-

pharmaceutical DS and DP manufacturing (API not in scope)

• Characterization of materials of construction / Chemical characterization of

components

• Not for qualification of materials

• Risk evaluation matrix (example in <1665>) to classify components into three risk

categories

• High risk components => application of standard extraction protocol

• Concept of the comparator (component / system used to produce approved /

marketed DP) => no further assessment required

• USP <665> versus BPOG extractables protocol

(see also: Ding et al, Pharmaceutical Engineering, 2014, 34 (6), 1-11)



• USP <1663> “Assessment of extractables associated with pharmaceutical packaging /

delivery systems”

• Any leachables assessment should be preceded by an extractables assessment

• Two critical parameters during an extractables study, i.e. “generation of the extract” and “testing the extract”

• USP <1664> “Assessment of drug product leachables associated with pharmaceutical

packaging / delivery systems”

• Modified FDA risk-based approach to consideration of leachables

=> Downgraded some dosage forms with regards to “likelihood of packaging component-dosage form interaction”

• Both: Scientific principles, not prescriptive, descriptive (best practices), generic

• Principle concept of the AET (derived from safety threshold) only in <1664>



• ICH M7 “Assessment and control of DNA reactive (mutagenic) impurities in

pharmaceuticals to limit potential carcinogenic risk”

• Evaluation of genotoxic impurities (that have generated during the synthesis of small molecule APIs)

• Principles can be applied to toxicological assessment of leachables

• TTC (lifelong, daily exposure) of 1.5 μg/day (parenterals) corresponding to a theoretical excess cancer risk of <1 in 100,000 over a lifetime

• Less than lifetime (LTL) exposure:

(see: Paskiet et al, PDA J Pharm Sci and Tech, 2013, 67 430-447)




E&L assessment workflow

Listing all contact

materials

Assessing contact

conditions

Calculating a risk score

for each material

Material Risk evaluation

Laboratory

E&L assessment

Compound

exceeding a

threshold

Extractables study

Leachables study

Simulated in-use leachables

study

Structure elucidation

Tox assessment

Assessing vendor data

Experimental study

Experimental

study

• Listing of all materials in contact with the process stream

• Chromatographic skids / resins, membranes, filters, tubing, intermediate storage bags, connectors, DS storage containers, DP container closure system, etc.

• Establishment / description of contact conditions

• Duration of contact, pH and polarity of contact solution, temperature, etc.

• Input from process experts is necessary

• Very time consuming


Mapping the DS / DP process

• Process conditions considered:

20

Material risk evaluation

Risk parameter Condition encountered in the manufacturing process Rating Weight

Distance along theprocess stream (DAS)

Upstream Materials used after vial thaw, e.g. during inoculation, expansion, production, harvest, plasma and solution preparation 1

0.4

Downstream

Materials used after harvest and before the second last dedicated purification step. Dedicated purification steps are affinitychromatography, ion exchange chromatography, chromatography based on hydrophobic interaction and diafiltration. Process expertsmight identify other dedicated purification steps.

3

Materials used after (and including) the second last dedicated purification step (usually TFF or chromatography) up to (and including) thelast dedicated purification step. Dedicated purification steps are the same as above.

5

Materials used after the last dedicated purification step (usually TFF or chromatography), including microfiltration, filling and storage ofbulk drug substance (BDS). Dedicated purification steps are the same as above.Drug product manufacturing, fill/finish: Materials in contact with BDS after removal from the final DS storage container, and materials incontact with formulations that are added to the BDS, up to filling of DP into a container closure system.

9

Exposuretemperature (ET)

< 0°C 1

0.150 to 8°C 3> 8°C to 30°C 5> 30°C 9

Exposure duration(ED)

Transient (≤ 60 minutes) 1

0.15Short (≤ 24 hours) 3Medium (≤ 7 days) 5Long (>7 days) 9

Process fluid interaction (PFI)

Limited penetration into polymeric component (i.e. water) 1

0.15

Low solvation power or low penetration of polymeric component, e.g. neutral pH without organics, surfactants, etc. 3

Medium solvation power or medium penetration of polymeric, component, e.g. surfactant, low-concentration organics, high/low pH solutions without organics, detergents

5

High solvation power or high penetration of polymeric component 9

Dilution ratio (DR)

< 1 x 10-3 m2/L 1

0.151 x 10-2 to 1 x 10-3 m2/L 31 x 10-1 to 1 x 10-2 m2/L 5> 1 x 10-1 m2/L 9

Pharma & Biotech | Dr. Martina Ribar Hestericová | 26 September 2019

Adapted from BPOG best practices for evaluating E&L risk from single use systems

• Risk score = (Rating DAS * 0.4) + (Rating ET * 0.15) + (Rating ED * 0.15) + (Rating PFI * 0.15) + (Rating DR

* 0.15)

• Follow up for risk mitigation depends on the risk score:

21

Risk calculation

E&L risk assessment

Risk Score Risk category Requirements for risk mitigation

1.0 to 3.6 Low No requirements

3.7 to 6.2 MediumSafety documentation of the material has to be consulted. Biocompatibility (e.g.compliance to USP <87> or >88> commonly referred to as USP Class VI, ISO 10993) has tobe demonstrated

6.3 to 9.0 HighQuantitative assessment of extractables and / or leachables data considering analyticalthresholds derived from safety thresholds


Adapted from BPOG best practices for evaluating E&L risk from single use systems

22

Practical considerations

Laboratory E&L assessment

Long term contact (container closure systems)

Extractables / Leachables studies

Short term contact (manufacturing / administration materials)

simulated in-use leachables studies

Vials (Glas & Stopper), pre-filled or Luer type syringes (Glas or plastic & Stopper)Cartridges (…)

Filters, tubing, gaskets

Administration sets

DS storage bags (storage <0°C)


Images: Lonza, Science-exercises.eu, or creative commons licence

• Extractables study

• Performed on materials with long contact time where one study cannot realistically simulate contact (CCS for DP storage)

• Performed under exaggerated conditions (solvent strength, temperature), allows for extrapolation

• Leachables study

• Performed on materials with long contact time (CCS for DP storage)

• Screening study in addition to the extractables study

• Target leachables study for compounds that have been identified as potential safety risk

• Simulated in-use leachables study

• Performed on materials with transient contact time

• Typically performed on DS / DP process materials and administration materials

• Special consideration: CCS for storage of DS formulation in frozen state

• Performed under simulation conditions

23

Extractables vs leachables vs simulated in-use leachables study


• The biopharmaceutical formulation – usually containing the active protein at high concentration (e.g. up to 150 mg/mL) – cannot be analyzed for technical reasons (usually)

• Therefore, alternative test solutions (surrogate solutions) are used

• Placebo / vehicle – biopharmaceutical formulation with the same composition and pH, but not containing the active protein → for leachables study

• 0.1% PS20 solution – high surfactant concentration – serves as a worst case →for leachables and extractables study


Choice of surrogate solutions


• Incubation of disposable syringe with water (top) and with 0.1% PS20

• => Presence of surfactant has strong influence on leachables propensity


Choice of surrogate solutions


RT: 0.00 - 14.00

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14Time (min)

-400000

-350000

-300000

-250000

-200000

-150000

-100000

-50000

0

uAU

-400000

-350000

-300000

-250000

-200000

-150000

-100000

-50000

0

uAU

1.220.65 1.88 2.17

RT: 8.78

1.220.65 1.64 2.17

NL:4.31E5nm=219.5-220.5 PDA el_084_2016_003

NL:4.29E5nm=219.5-220.5 PDA EL_084_2016_004

• AET is the threshold at or above which a chemist should identify a particular leachable and/or extractable and report it for potential toxicological assessment

• Proportional to the SCT

• SCT: Safety concern threshold (= 1.5 μg per treatment / day)


Setting up thresholds


General analytical approach for E&L screening

Laboratory E&L study

VOC volatile organic substances

SVOC semi-volatile

NVOC non-volatile

ICP/MS (OES) for elemental entities

Organic compounds Inorganic compounds / elements

Adapted from D. Jenke, TrAC Trends Anal. Chem. 2018, 101, 56–65.

• E&L assessment’s purpose:

• Guarantee patients’ safety

• Convince HAs that patient’s safety is guaranteed

• API’s efficacy and stability is not altered

• Following a certain workflow for E&L assessment is beneficial

• Consultation of guidelines

• Risk assessment:

• Mapping of manufacturing / storage / administration process

• Risk mitigation strategies

• Laboratory E&L studies guided by toxicological thresholds

• Proper documentation / justification of activities


Summary and outlook

E&L assessments

• Conclusion

• E&L assessment is complex, time intense

• E&L assessment should be performed by experts!


Summary and outlook

E&L assessments

• Michael Jahn

• The entire Forensic chemistry group at DPS


Acknowledgements


Thank you

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leachables and extractables: from regulatory expectations to … · 2019-10-04 · drug product...

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