Extractable and leachables

EXTRACTABLE AND
LEACHABLES STUDIES
Saikiran Koyalkar
Email: Saikiran.kiran78@gmail.com
saikiran.kiran78@gmail.com 1

REFERENCES:
• PQRI - Safety Thresholds and Best Practices For Extractables and
Leachables In Orally Inhaled And Nasal Drug Products
• FDA - Guidance for Industry Container Closure Systems for
Packaging Human Drugs and Biologics

DO YOU EVER THROUGHT WHAT
YOU ARE TAKING IS SAFE ?
•Food
•Drugs

DO YOU EVER THOUGHT THE
PACKING MATERIAL USING FOR
FOOD AND DRUGS ARE SAFE ?

CONTAINERS/PACKING MATERIALS
WHAT IS PACKING MATERIAL ?
A packaging component means any single part of a container closure
system
A primary packaging component:
packaging component that is or may be in direct contact with the dosage
form.
A secondary packaging component:
a packaging component that is not and will not be in direct contact with
the dosage form.

HOW PACKING MATERIAL SHOULD
BE ?
• Packing material should be Suitable for intended use.
• protect the dosage form
• compatible with the dosage form
• composed of materials that are considered safe for use with
the dosage form and the route of administration

HOW DO YOU ENSURE PACKING MATERIAL
USED FOR DRUG AND/OR FOOD ARE SAFE ?

REQUIREMENT
•The examination of Extractable and Leachable
substances is extremely important for the
protection of patients and for regulatory
documentation such as the FDA and EMA.

REQUIREMENT
• The Federal Food, Drug, and Cosmetic Act (the Act) mandates the
need for adequate information related to packaging materials. Section
501(a)(3) of the Act states that a drug is deemed to be adulterated "if
its container is composed, in whole or in part, of any poisonous or
deleterious substance which may render the contents injurious to
health...."

EXTRACTABLE
• Extractables are defined as container-closure contaminants
that can be extracted from packing materials under ‘forcing’
conditions, ie, high temperatures and pressures, organic
solvents, etc.

LEACHABLES
• “Leachable in OINDP are compounds which are present in
the drug product due to leaching from container/closure
system components.”
• Leachable are often a subset of, or are derived directly or
indirectly from Extractable.”

SOURCES OF EXTRACTABLE
• Sources of extractable are plastic and elastomeric
components (monomers, polymeric initiators, plasticizers,
etc.) ink and adhesives (label) and degradation products
(processing, storage, sterilization, stabilizers)

SOURCES OF EXTRACTABLE
• Metal components
• Elastomeric container/closure system components
• Plastic/polymeric container/closure system components
• Processing aids
• Blisters or capsules containing individual doses of drug product
• Labels

WHY EXTRACTABLE AND
LEACHABLE STUDY ?
• To ensure that there is no potential carcinogenic and non-
carcinogenic toxic chemicals coming out of packing material
and interacting with drug or food product stored.
• This Leachable study will be performed during the stability
studies of drug or food product.

EXTRACTABLE AND LEACHABLES
STUDIES
Pick targets (Extractable) :
Eg:
• Volatile organic compounds
• Semi volatile organic compounds
• Elastomers
• Plasticizers
• Nitrosamine's

STUDIES
• Poly aromatic hydrocarbons
• Anti-Oxidants
• Trace elements
• Phthalates
• 2-mercaptobenzothiozole
• Anions such as chloride , fluoride and Bromide
• Etc…

STUDIES
• Use appropriate extraction techniques
Eg: microwave digestion
soxhlate extraction
etc..
With appropriate solvents : Non-Polar, Mid-polar and Polar

STUDIES
• Use multiple techniques if necessary
Eg: GC-MS/MS
GC-MS/HS
LC-MS/MS
ICP-MS
Ion chromatography
Etc..

STUDIES
• Report the detected quantity of analytes which are performed in the
Quantitative mode.
• If analysis performed in qualitative mode compare the detected
masses with NIST library data based and report the probable detected
compounds

STUDIES
• Develop a method for the detected compounds in drug product which
is going to be stored in the container.
• Validate the method in drug products after completion of method
development

STUDIES
Calculate the AET
The AET is designed to determine how low one should go in a given
leachables profile to identify, quantify and evaluate individual leachables.
Calculation of Analytical estimated threshold ( AET) based on the daily dose,
total no. of doses in container
The AET will vary depending on
(i) the particular drug product configuration and
(ii) the method(s) used to detect and quantify the extractables and leachables
• Set the AET > LOQ

Examples : AET Calculation - Nasal Spray
Drug Product
•120 labeled actuations per canister
•Dose: 4 actuations per day
•Fill volume = 10mL

Eg: AET Calculation - Nasal Spray Drug
Product
• Estimated AET =
0.15µ𝑔
𝑑𝑎𝑦
𝑋 120 labelled actuations/ container
= 4.5µ𝑔/container
=
4.5µ𝑔 / container
10𝑚𝐿/𝑐𝑜𝑛𝑡𝑎𝑖𝑛𝑒𝑟
= 0.45 µ𝑔/mL

EVALUATION OF SAFETY CONCERNED
THRESHOULD
• Scientifically justifiable safety evaluation and qualification thresholds
for leachables in OINDP can be established.
• The PQRI Working Group proposes a Safety Concern Threshold
(SCT) of 0.15 mg per day, and a Qualification Threshold (QT) of 5 mg
per day for an individual leachable in an OINDP.
• The SCT is defined as the threshold below which a leachable would
have a dose so low as to present negligible safety concerns from
carcinogenic and non-carcinogenic toxic effects.

Leachable Testing- Goals
1. To understand the trends in drug product leachables levels over the
shelf-life of the product.
2. To determine maximum leachables levels up to the proposed shelf-
life.
3. To support a comprehensive safety evaluation of the drug product
leachables.

THANK YOU

Extractable and leachables

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