PDA Training Course Extractables & Leachables

25-26 April 2024

Introduction to Extractables & Leachables

Dr. Dries Cardoen

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Setting the stage

What is expected from packaging materials for drug products?

Working towards a definition of E&L

Do we need to be worried about packaging materials?

Potential suspects and case studies

How does an E&L study look like?

Analytical chemistry and toxicology in tandem

What are the regulatory requirements for safety of a CCS and mfg
equipment?
Browsing through the regulatory landscape

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What is expected from packaging

materials for drug products?

Working towards a definiton of E&L

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What is expected from Container/Closure Systems?

Guidance for Industry – CCS for packaging human drugs and

biologics
May 1999!

The selected Container / Closure system must be

“suitable for its intended use”

Protection Compatibility Performance Safety

A C/C-system that is suitable for 1 Drug Products, may not be suitable for another DP!

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What is expected from Container/Closure Systems?

• CCS should protect DP from factors that can cause degradation
Solvent evaporation

Primary packaging
O2
H2O
microbes
dirt

Light
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What is expected from Container/Closure Systems?

• CCS should protect DP from factors that can cause degradation
o Secondary packaging! Solvent evaporation

Secondary packaging
Primary packaging
O2
H2O
microbes
dirt

Light

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What is expected from Container/Closure Systems?

• CCS should be compatible with the DP
o No interactions that cause detoriation of quality of DP or CCS!
Material – DP interactions

API or Excipient

Packaging material

Drug product
API or Excipient

pH

Colour

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What is expected from Container/Closure Systems?

• CCS is often designed to do more than just store the DP
o Functionality and Drug Delivery

Facilitating drug delivery

Minimizing Patient Ease of

waste compliance use

Many CCS are combination products!

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What is expected from Container/Closure Systems?

• CCS should be constructed from materials that do not leach harmful substances
o Migration of impurities! Material – DP interactions
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What is expected from Container/Closure Systems?

• Each aspect of the design of a CCS has a potential impact on its safety!
o Safety is not an isolated parameter!

Packaging
components

Materials of
construction
+
Processing

Separate Chapter
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What is expected from Container/Closure Systems?

• E&L study is a qualitative and quantitative investigation of migrating
compounds from contact materials into DP
o Contact materials: CCS + manufacturing equipment
o Impact on safety and quality
Manufacturing equipment Container/closure system
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Do we need to be worried?

Case Studies and Potential Suspects

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Do we need to be worried?

Extractables and leachables

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Are interaction concerns for real?

• Degree of concern depends on composition DP and route of administration

Degree of concern
Separate Separate
Chapter Chapter

OINDPS
Drug tablets and capsules Parenteral drug products
Aerosol (driving gas)
Solid drug product Liquid drug product (aqueous)
Strong interaction with CCS
Weak interaction with CCS Intermediate interaction with CCS
Chronic administration to
Oral administration Administration to bloodstream
target organ
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What is expected from Container/Closure Systems?

• Potential compounds of concern – example of PFS
Rubber stopper
• Halogenated rubber oligomers – alkylating agents
• PolyNuclear Aromatics (PNA’s) from carbon black – carcinogenic
• Nitrosamines and sulfur-holding compounds from curing system – carcinogenic
• Iron – oxidative degradation of proteins*
• Aromatic antioxidants – toxic

Chapter 2
Glass barrel
• Barium and Aluminum – particle formation*
• Silicon oil – protein aggregation*
Staked needle
• Residual tungsten – Protein degradation*
• Acrylates from incomplete curing – reactive and toxi

* Presented By I. Markovic, “Regulatory Perspective on Extractables & Leachables for Biologics, Quality Perspective” PDA E/L-Workshop,
Brussels , 2014
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What is expected from Container/Closure Systems?

• Bisphenol A and DEHP – (in)famous examples of impurities from plastic
Leaching of the plasticizer di(2-ethylhexyl)phthalate
(DEHP) from plastic containers and the question of
human exposure.
Di(2-ethylhexyl)phthalate (DEHP) is a widely used plasticizer to render poly(vinyl chloride) (PVC) soft and
malleable. Plasticized PVC is used in hospital equipment, food wrapping, and numerous other commercial and
industrial products. Unfortunately, plasticizers can migrate within the material and leach out of it over time, ending
up in the environment and, frequently, the human body.

BPA, chemical used to make plastics, found to leach

from polycarbonate drinking bottles Into humans -
Exposure to BPA May Have Harmful Health Effects
Boston, MA — A new study from Harvard School of Public Health (HSPH) researchers found that participants who
drank for a week from polycarbonate bottles, the popular, hard-plastic drinking bottles and baby bottles, showed a
two-thirds increase in their urine of the chemical bisphenol A (BPA). Exposure to BPA, used in the manufacture of
polycarbonate and other plastics, has been shown to interfere with reproductive development in animals and has
been linked with cardiovascular disease and diabetes in humans. The study is the first to show that drinking from
polycarbonate bottles increased the level of urinary BPA, and thus suggests that drinking containers made with
BPA release the chemical into the liquid that people drink in sufficient amounts to increase the level of BPA
excreted in human urine.
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• Eprex = Human Recombinant EPO

• introduced in late ‘80 early ’90 – Janssen Cilag

• Increase Hematocrit (RBC-count) in CKD

Patients

• Until ’98: no side effects

• From ‘98 onwards: increased incidence of PRCA

• Caused a drop in Hematocrit (instead of an
increase)
• Immune response

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< 1998 > 1998

Treatment of CKD
Patients
SC injection
FORMULATION Serum Albumin Polysorbate 80
(Protein Stabilizer)
Incompatible
CONTAINER
CLOSURE SYSTEM

Leachables from the

Leachables are Formulation Dependent rubber plunger
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Eprex case: Incidents of AB-mediated Pure Red Cell Aplasia

Changes in Coated
Formulation Plungers

CONTAINER Incompatible
CLOSURE SYSTEM

80
Antibody mediated

70
60
50
40
30
20
PRCA

10
0
1
1989 2
90 3
91 4
92 593 694 7 958 969 10
97 11
98 1299 132000
14 0115 02
16
03 04

Red Blood Cell levels substantially reduced because of an

Anti-body mediated immune response
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QUESTION: Who could have predicted an anti-body

mediated immune response, based upon those analytical
data?

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Mode of action - Hypothesis in the early work:

Leachables (one or more) could cause adjuvant-like properties,
“boosting” an immune response, which is causing ADA’s (Anti-Drug-
Antibodies) to be formed

ADA’s attacked both endogenous & exogenous EPO

ultimately resulting in a substantial decrease of Red Blood Cells
(PRCA/Anemia)

However, the “adjuvant like properties” of the detected compounds

were studied in animal models, but no ADA’s were observed.

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FDA Guidance for Industry (2014) Immunogenicity –

Therapeutic Proteins

Mode of Action -
New Line of Thinking:

Reactive Leachables may form covalent bonds with

Biologics and may lead to Immuno Responses

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What is expected from Container/Closure Systems?

• Tribromoanisole case – tertiary packaing affects quality of DP
38,000 more bottles of Lipitor recalled over odor
complaints
(CNN) -- Pfizer is recalling an additional 38,000 bottles of the cholesterol-fighting drug Lipitor after reports of an
odor linked to the packaging bottles, the drug company said in a statement…. "Research indicates that a major
source of TBA appears to be 2, 4, 6-tribromoanisole(TBP), a chemical used as a wood preservative," the company
said. "Although TBP often is applied to pallets used to transport and store a variety of products, Pfizer prohibits the
utilization of TBP-treated wood in the shipment of its medicines."

34,000 Tylenol bottles recalled for musty

smell
NEW YORK (CNNMoney) -- Johnson & Johnson is recalling yet another batch of Tylenol
medicines due to consumer complaints about a musty, moldy smell....
The company said at the time that the smell was caused by trace amounts of a chemical called
2,4,6-tribromoanisole, which is applied to wooden pallets that are used to transport and store
packaging materials….

Glumetza Recall: 52 Lots of Diabetes Drug

May Have Chemical Contamination
More than 200,000 bottles of the diabetes drug Glumetza have been recalled due to the same
chemical contamination from wood pallets that led to a Tylenol recall late last year.

2,4,6-Tribromoanisole (a wood preservative) contamination of DP due to

lack of good barrier properties of primary packaging
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What is expected from Container/Closure Systems?

• Protein drug products require special care
o Administration by injection is among those of highest concern

o Likelihood of interaction between packaging component and injectable dosage is high

o Biologics are complex

✓ Large molecular weights
✓ Abundance of binding sites on the surface (hydrophilic and hydrophobic)
✓ Heterogeneous mixtures

o Biologics are sensitive to structural modifications

✓ Safety considerations (immunogenicity)
✓ Efficacy considerations (loss of activity, formation of neutralizing antibodies)
✓ Quality considerations (protein aggregates, stability)
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How does an E&L study look

like?

Analytical Chemistry and Toxicology in Tandem

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The flow of an E&L study

N° of compounds involved

• Analytical
What arechemistry and toxicology
the chemical in tandem
impurities of the packaging? 20-100
Assessing the risk
• Extractables to –the
study patient
focus through 4 basic questions:
on identification
EXT

• What are the targets of concern? 3-20

TOX • Comparison of EXT concentrations with safety concern thresholds

• Which compounds are migrating into the drug product? 1-5

LEA • Leachables study – focus on quantitation

• What is the risk to the patient? 0

TOX • Toxicological evaluation of leachables

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The flow of an E&L study

EXT What are the chemical impurities of the packaging?

Extractables study = analytical study of the packaging
Generating the extract
Packaging components in final form
TOX
– ETO, steam, X-ray, washed, siliconized, ...

Worst-case approximation of DP-CCS interaction in 3 parameters

LEA – Solvents (pH and polarity) or DP vehicle
– Temperature and time
– Extraction stoichiometry
Separate Chapter
TOX

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The flow of an E&L study

What are the chemical impurities of the packaging?

Extractables study = analytical study of the packaging
EXT
Analyzing the extract - Screening
➢Methods designed for the detection of as many compounds as possible elements
➢Semi-quantitative results NVOC
TOX ➢Supplemented with targeted techniques based on processing and MOC SVOC
VOC
orthogonal screening

LEA

TOX

Separate Chapter
Main purpose of an EXT study is Identification of migrating compounds! 28
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The flow of an E&L study

Classification and Comparison of concentrations with thresholds

EXT What are the compounds of concern?

In silico evaluation of extractables data General toxicity
Extractables data
Highest treshold

TOX
QSAR
software Sensitizers, irritants

LEA
Carcinogens, mutagens
Lowest threshold
TOX

Compounds > class-specific threshold → target compounds for leachable study!

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The flow of an E&L study

Analyis of the drug product
Which chemical impurities are migrating into the drug product?
Leachables study

EXT
Separate Chapter
targeted
screening
TOX

LEA
Target compounds Unexpected leachables
Quantitative Semi-Quantitative
Compound-specific tresholds Safety Concern Threshold / Qualification Threshold
TOX
Main purpose of a LEA study is Quantitation of migrating compounds!
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The flow of an E&L study

Toxicological assessment of LEA data
All leachables > conservative treshold should be subjected to toxicological assessment
Comparison of worst-case patient exposure with Permitted Daily Exposure (PDE)
In most cases: conservative threshold < PDE

What is the risk to the patient?

EXT Toxicological evaluation of leachables

TOX
Tox
assessment
LEA PDE

TOX
Separate Chapter

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The flow of an E&L study

Extractables study on CCS

Analytical chemistry and toxicology in tandem Let’s recap!

Leachables study on DP

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What are the Regulatory

Requirements for Safety of a CCS?

Browsing through the Regulatory Landscape

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Regulatory Requirements
• Two types of Regulatory Requirements

What kind of information should be provided?

US guidances
EU guidelines - GMP
Code of Federal Regulations
ICH

How can the testing be performed?

Pharmacopeias (USP, JP, EP, ...)
Standard Organizations (ISO)
Recommendations of Workgroups (PQRI
Consortia
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Regulatory Requirements

What kind of information should be provided?

PRIMARY PACKAGING
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Regulatory Requirements - What

PRIMARY PACKAGING
• The What Requirements for Primary Packaging
REGULATORY ASPECTS – PARENTERALS – NON-LIMITATIVE LIST

<1999: 21CFR 211.94(a) “DRUG PRODUCT CONTAINERS AND CLOSURES”

...not reactive, additive, absorptive to alter safety, identity, strength, quality or purity of drug...

1999: “CONTAINER/CLOSURE SYSTEMS FOR PACKAGING HUMAN DRUGS AND BIOLOGICS” (FDA-
Guidance for Industry)

2003: EU COMMISSION DIRECTIVE 2003/63/EC, (§ 3.2.2.2 g)

CCS-information is part of the Market Authorization dossier.

2005: “GUIDELINE ON PLASTIC IMMEDIATE PACKAGING MATERIALS” (EMEA Guideline)

Contains “Decision Tree” for different dosage forms

2006: ICH Q8 “PHARMACEUTICAL DEVELOPMENT”, §2.4 CCS

2014: USP <1663> (Extractables) & USP <1664> (Leachables)

2015: ICH M7: DNA reactive impurities in Pharmaceuticals

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Regulatory Requirements - What

PRIMARY PACKAGING
• The What Requirements for Primary Packaging
REGULATORY ASPECTS – PARENTERALS – NON-LIMITATIVE LIST

<1999: 21CFR 211.94(a) “DRUG PRODUCT CONTAINERS AND CLOSURES”

...not reactive, additive, absorptive to alter safety, identity, strength, quality or purity of drug...

1999: “CONTAINER/CLOSURE SYSTEMS FOR PACKAGING HUMAN DRUGS AND BIOLOGICS” (FDA-
Guidance for Industry)

2003: EU COMMISSION DIRECTIVE 2003/63/EC, (§ 3.2.2.2 g)

CCS-information is part of the Market Authorization dossier.

2005: “GUIDELINE ON PLASTIC IMMEDIATE PACKAGING MATERIALS” (EMEA Guideline)

Contains “Decision Tree” for different dosage forms

2006: ICH Q8 “PHARMACEUTICAL DEVELOPMENT”, §2.4 CCS

2014: USP <1663> (Extractables) & USP <1664> (Leachables)

2015: ICH M7: DNA reactive impurities in Pharmaceuticals

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Regulatory Requirements - What

PRIMARY PACKAGING
• The What Requirements for Primary Packaging - FDA
o Required information depends on route of administration and CCS-DP interaction
o From FDA guidance (1999) to USP <1664> Separate Chapter
Examples of Packaging Concerns for Common Classes of Drug Products
Degree of Concern Likelihood of Packaging Components – Dosage Form Interactions
Associated with the
Route of High Medium Low
Administration
Inhalation Aerosols Injections and Sterile Powders and
and Sprays Injectable Powders for Injection;
Highest
Suspensions; Inhalation Powders
Inhalation Solutions
Transdermal Ophthalmic Solutions -
Ointments and and Suspensions;
High
Patches Nasal Aerosols and
Sprays
Topical Solutions and - Oral Tablets and Oral
Suspensions, Topical (Hard and Soft Gelatin)
Low and Lingual Aerosols, Capsules; Topical
Oral Suspensions and Powders; Oral
Solutions Powders
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Regulatory Requirements - What

PRIMARY PACKAGING

• The What Requirements for Primary Packaging - FDA

o Going through the FDA/USP matrix

LIKELIHOOD OF INTERACTION = LOW

Packaging Component - Dosage Form

DEGREE OF CONCERN
FOR ROUTE OF ADMINISTRATION = LOW

e.g. Oral solutions/suspensions, Oral Tablets/Capsules/Powders…

CERTIFICATE OF ANALYSIS may be sufficient

➢ COMPENDIAL testing
➢ ROUTINE QC testing
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Regulatory Requirements - What

PRIMARY PACKAGING
• The What Requirements for Primary Packaging - FDA
o Going through the FDA/USP matrix

LIKELIHOOD OF INTERACTION = HIGH

Packaging Component - Dosage Form

DEGREE OF CONCERN
FOR ROUTE OF ADMINISTRATION = HIGH

e.g. Inhalation Aerosols (MDI, DPI, Nasal Sprays), Injections, Injectable

suspensions
(Parenterals : Pre-filled syringes, IV bags…), Ophtalmic
solutions/suspensions…

CERTIFICATE OF ANALYSIS (compendial and routine testing)

EXTRACTABLES and/or LEACHABLES testing required

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Regulatory Requirements - What

PRIMARY PACKAGING
• The What Requirements for Primary Packaging - FDA
o Important remark on FDA guidance

The requirements in the FDA Guidance Document

“Container Closure Systems for Packaging Human Drugs and Biologics” of 1999
do NOT reflect the current (2015) FDA/USP requirements
for E/L Testing and Documentation
NOT ONLY EXTRACTABLES evaluation => Consider LEACHABLES STUDIES!
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Regulatory Requirements - What

PRIMARY PACKAGING
• The What Requirements for Primary Packaging - EMEA
o Going through the decision tree (EM(E)A Guideline on “Plastic Immediate Packaging Materials” of 2005)
Route of administration
CCS-DP interaction
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Regulatory Requirements - What

PRIMARY PACKAGING
• The What Requirements for Primary Packaging - EMEA
o Going through the decision tree: solid dosage forms – low requirements
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Regulatory Requirements - What

PRIMARY PACKAGING
• The What Requirements for Primary Packaging - EMEA
o Going through the decision tree: liquid dosage forms – high requirements
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Regulatory Requirements - What

PRIMARY PACKAGING
• The What Requirements for Primary Packaging - EMEA
o Going through the decision tree: liquid dosage forms – high requirements

Liquid dosage forms

E.P. COMPENDIAL TESTING IS REQUIRED BUT NOT SUFFICIENT.

ADDITIONAL REQUIREMENTS
EUROPEAN PHARMACOPOEIA TESTS
EXTRACTION STUDIES
INTERACTION STUDIES (INCLUDING §5.1 MIGRATION STUDIES)
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Regulatory Requirements - What

PRIMARY PACKAGING
• The What Requirements for Primary Packaging - EMA
o Important remarks on EMA packaging guideline
Not for Elastomers (?) = > In reality: ALSO fo rubbers

If a Material is described in the E.P. and if it complies with the specifications

therein, no Extractable testing may be needed.
≠ THE ACTUAL POSITION OF EUROPEAN REGULATORS

If Extractable Testing shows only compounds with low risk (at low concentrations)
no leachable study is necessary.
≠ THE ACTUAL POSITION OF EUROPEAN REGULATORS
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Regulatory Requirements - What

What kind of information should be provided?

Manufacturing
equipment
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Regulatory Requirements - What

Manufacturing
• The What Requirements for Manufacturing Equipment equipment
U.S.
Title 21 of the Code of Federal Regulations (CFR) 211.65 (1)
“...Equipment shall be constructed so that surfaces that contact components, in-process materials or drug
products shall not be reactive, additive or adsorptive so as to alter safety, identity, strength, quality or
purity of the drug product beyond the official or other established requirements...”

EUROPE
ICH Q7 – GMP Practice Guide
“...Equipment should not be constructed so that surfaces that contact raw materials, intermediates or API’s
do not alter the quality of the intermediates and API’s beyond the official or other established
specifications...”

EU – Good Manufacturing Practices

“...Production Equipment should not present any hazard to the products. The parts of the production
equipment that come into contact with the product must not be reactive, additive... That it will affect the
Quality of the Product...”
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Regulatory Requirements - What

Manufacturing
• The What Requirements for Manufacturing Equipment equipment

OBSERVATIONS
The CFR 211.65 and GMP’s do not only refer to the impact on Safety, but also on:
➢ Quality
➢ Purity
➢ Strength (e.g. Adsorptive behavior)
➢ Reactive behavior
➢ Additive behavior

Reasoning of Regulators
➢ Know your Process
➢ Know the impact of SUS on the quality of the Product
➢ Prove that you have made an assessment

Disposable Production is fairly new, may trigger additional questions

For Safety Considerations, the main concern for SUS systems is their contribution to potential Immuno-
responses (IMMUNOGENICITY) to the Drug Product
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How should the test be performed?

How can an adequate testing strategy – to qualify a

container / closure system from an E/L perspective - be put
together?
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Regulatory Requirements – HOW?

• “HOW” requirements:
• US Pharmacopoeia (USP)

• European Pharmacopoeia (EP)

• ISO 10993 Standards (Biocompatibility - Medical Devices)

• PQRI – Product Quality Research Institute

• OINDP Orally Inhaled and Nasal Drug Products
• PDP/ODP: Parenteral Drug Products/Ophthalmic Drug Products

• BPSA Bio-Process Systems Alliance (SU Systems)

• BPOG Biophorum Operations Group (SU Systems)

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Regulatory Requirements – HOW?

• US Pharmacopoeia (USP) Separate Chapter

MANDATORY TESTS (<1000)

<381> Elastomeric Closures for Injections

<661> Containers (still partially under revision)

<661.1> Plastic Material of Construction (FINAL)
COP/COC, PA 6, PC, PE, PET/PETG, EVA, PP, PVC
<661.2> Plastic Packaging Systems for Pharmaceutical Use (FINAL)
<661.3> = > <665> Manufacturing Systems (UNDER REVIEW)
<661.4> Devices (UNDER DEVELOPMENT)

<87> Biological Reactivity Tests, In Vitro (Cytotox tests)

<88> Biological Reactivity Testing, In Vivo (Class Tests)

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Regulatory Requirements – HOW?

• European Pharmacopoeia (EP)

3.1 Materials used in the manufacture of containers

3.1.1.1 PVC for human blood (components) containers

3.1.1.2 PVC for human blood (components) tubing sets
3.1.3 Polyolefines
3.1.4 PE without additives containers for parenteral/ophthalmic preps
3.1.5 PE with additives containers for parenteral/ophthalmic preps
3.1.6 PP containers for parenteral/ophthalmic preps
3.1.7 EVA for containers and tubing for parenteral/ophthalmic preps
3.1.9 Silicone elastomer for Closures and Tubing
3.1.10 & 11 non-plasticized PVC
3.1.14 Plasticized PVC
3.1.15 PET
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Regulatory Requirements – HOW?

• European Pharmacopoeia (EP)
3.2 Containers

3.2.1 GLASS containers for pharmaceutical Use

3.2.2 Plastic Containers/Closures for Pharmaceutical Use
3.2.2.1 Plastic Containers for aq. solutions for parenteral infusion
3.2.3 Sterile plastic containers for human blood (components)
3.2.4 Empty Sterile containers of plasticized PVC for human blood
3.2.5 Sterile containers of plasticized PVC for human blood,
containing anticoagulant
3.2.6 Sets for the transfusion of Blood and Blood components
3.2.8 Sterile single-use plastic syringe
3.2.9 Rubber Closures
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Regulatory Requirements – HOW?

• Compendial testing (USP and EP)

CHARACTERISTICS of Physicochemical Compendial tests:

Well Defined Analytical Approach:

• Sample Preparation (Extraction Method, Time, Temperatures...)
• “GROUP PARAMETER” Analyses (Acidity/Alkalinity, Residues, Reducing Substances,
Absorbance, Turbidity...)
• In some cases: Individual Compound Analyses ( Polymer Additives, Extractable/Total
Metals...)
• Sometimes: Identification (e.g. FTIR)

PASS / FAIL Criteria!!

Compendial tests follow a “COOK BOOK” Approach!!
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Regulatory Requirements – HOW?

• Compendial testing (USP and EP)
STRENGHTS of Pharmacopoeial Compendial Tests
armacopoeial Compendial Tests

➢ Provide Basic Information on the Quality of Materials

➢ Clear PASS / FAIL Criteria

➢ Can be used in the development of a new MATERIAL formulation

➢ Can be used to monitor the quality in production

(e.g. In combination with physical tests)

➢ Assists in the initial safety assessment of a material

(eg. Additives may define which compounds may be encountered as leachables)
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Regulatory Requirements – HOW?

• Compendial testing (USP and EP)
LIMITATIONS of Pharmacopoeial Compendial Tests

➢ Sample preparation: not always relevant!

e.g. Rinsing procedure: loss of potential impurities (extractables)
WFI is not always to most relevant extraction Vehicle

➢ Group Parameters are not usable for Extractables Interpretation

e.g. E.P. Absorbance: Which compounds are Causing absorbance? What is their concentration?

➢ Limited information on individual compounds

e.g. E.P.: Polymer additives, Extractable total metals

➢ No detailed information on process impurities, polymer degradation compounds, additive degradation

compounds, oligomers, solvent residues...
Compendial testsing ≠ substitute for Extractables testing
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Regulatory Requirements – HOW?

• USP guidances monographs (>1000) Separate Chapter

<1661> Evaluation of Plastic Packaging – and Manufacturing Systems and their Materials of
Construction with respect to their Safety Impact

<1663> Assessment of Extractables Associated with PharmaceuticalPackaging/Delivery Systems

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

Systems

<1665> Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products
(Draft)
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Regulatory Requirements – HOW?

• Applicable ICH guidances
• ICH Q3D: Elemental Impurities (2014; Step 4)
• ICH Q6B: test procedures and acceptance criteria for biotechnological/biological products (1999)
• ICH Q5C: Quality of Biotechnology Products Stability of biotechnological/biological products (1996)
• ICH Q5E: Comparability of biotechnology/biological products subject to changes in their
manufacturing process (2005)
• ICH Q7A: GMP of APIs
• ICH Q8: Pharmaceutical Development (2006)
• ICH Q9: Quality Riks Management (2006)
• ICH Q10: Pharmaceutical Quality Systems (2008)
• ICH Q3C: Impurities: Residual Solvents (although no specific reference to C/C impurities)
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Regulatory Requirements – HOW?

• Other guidance documents
• ISO 10993 Standard (Biocompatibility - Medical Dev.)

• PQRI – Product Quality Research Institute

• OINDP Orally Inhaled and Nasal Drug Products
• PDP/ODP: Parenteral Drug Products/Ophthalmic

• BPSA Bio-Process Systems Alliance (SU Systems)

• BPOG Biophorum Operations Group (SU Systems)

• Guidance for Industry: Nasal Spray and Inhalation Solutions, Suspension and Spray Drug Products
– Chemistry Manufacuring and Controls Documentation, CDER (2002)

• Guidance for Industry: Pharmaceutical Quality of Inhalation and Nasal Products, Health Canada
(2006)

• Guidelines on the Pharmaceutical Quality of Inhalation and Nasal Products, EMA (2006)

• Draft Guidance for Industry: Metered Dose Inhalers (MDI) and Dry Powder Inhaler (DPI) Drug
Products. Chemistry, Manufacturing and Controls Documentation, CDER (1998)
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Dr. Dan Mellon – FDA - youtube

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Thank you!

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ICH Q3D: ELEMENTAL IMPURITIES

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ICH Q6B: test procedures and acceptance criteria for

biotechnological/ biological products (1999)
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ICH Q5C: Quality of Biotechnology Products Stability of

biotechnological/biological products (1996)
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ICH Q5E: Comparability of biotechnology/biological products

subject to changes in their manufacturing process (2005)
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ICH Q7A: GMP of APIs

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ICH Q8: Pharmaceutical Development (2006)

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ICH Q9: Quality Risk Management (2006)

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ICH Q10: Pharmaceutical Quality Systems (2008)