Reference Standards

PHARMACEUTICAL REFERENCE
STANDARDS
11th International Symposium

organised by the
European Directorate for the Quality of Medicines
& HealthCare (EDQM), Council of Europe
3-4 September 2012, Strasbourg, France
Session 3 – Presentations (Part 1)
Material Management / Technology

Changes
04/09/2012
September 2012,
Symposium Pharmaceutical Reference Standards
Managing Third Parties for the Preparation

and Maintenance of Reference Standards
Mr. Vaughn R. Stultz
Dr. Matthew Borer
Ms. Kimberley Dancheck
Mr. Michael Julius
Mr. David Lytle
Ms. Margaret McInerney
Deciding What to Outsource

Self-contained processes done together at one vendor
Missing or unique technical capabilities
Operations that have minimal oversight requirements
Well defined processes with minimal associated

difficulty
Processes that are performed infrequently or require

expensive equipment
Always keeping in mind cost and quality

Stultz, et. al.- Managing Third Parties for the Preparation and Copyright © 2012 Eli Lilly and Company 2
Maintenance of Reference Standards September 2012
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Expertise and Customer Service

• Find vendors who perform the
operations as a core part of their
business and deliver services with the
customer’s needs in mind
Examples of Outsourced Operations

with Respect to Reference Standards
Prepackaging and labeling of bulk material
Special synthesis of small molecules
IT Support
Disaster recovery storage
Physicochemical characterization tests (where site

certification is not required)
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Examples of Outsourced Operations

with Respect to Reference Standards
Processing and dispensing of routine customer orders
Vial lyophilization
Shipping dock services
Remote distribution centers
The level of third party oversight

required is determined by:
• Complexity
• Expertise
• Level of business integration
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High Level Oversight Considerations

Routine “joint management team” meetings
In-depth and higher frequency audits
Detailed master service agreement
Detailed performance metrics monitored
“Man in plant” for key operations
The key to a successful third party relationship

is based on the mutual understanding of
expectations.
Specifically, the third party should understand

the difference between Reference Standard and
Drug Substance / Drug Product manufacturing
and testing
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High Level Differences
Reference Standard Drug Substance or Drug Product
Intended use – laboratory control Intended use – human dosing

Limited regulatory requirements Extensive regulatory requirements
Limited registration commitment Extensive registration commitment
Closed system of users Open system of patients
Infrequent manufacturing Routine manufacturing
Overprotective packaging Packaging optimized for cost
Overprotective storage Storage optimized for convenience
Sterility typically unimportant Sterility typically vital
Documentation is critical! Documentation is critical!
Lessons Learned
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Real Examples: Problems when

Outsourcing
Instructions are too complex or there is insufficient
communication of expectations
• During preparation of a degraded suitability mixture, the caustic
solution was quenched prior to a sufficient extent of reaction,
resulting in a material incompatible with its intended use
Critical raw material requirements not identified

• Changing a water source led to observation of “extra” peaks during
the analysis of the reference standard, causing the batch to be
rejected
Real Examples: Problems when

Outsourcing
Inconsistent communication model
• A sample submission process that is in constant flux causing the
submission of materials for testing to be consistently incorrect
• Low/incorrect prioritization given to assignments, leading to missed
deadlines
Quality and Expertise

• Significant issues with reported analytical characterization data
• Simple, routine assignments required excessive guidance and
oversight
• Assumption that the third party understood more than they did,
leading to aggregation issues in the solubilization of a simple protein
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Real Examples: Benefits when

Outsourcing
Avoidance of Capital Spending
• Outsourcing of small-scale vial-lyophilized reference standards
Self-Contained Work
• Outsourcing of general characterization and monograph testing like
IR, UV, and thermal analysis, allowing focus internally on core
activities
Real Examples: Benefits when

Outsourcing
Staffing Flexibility and Expense
• There when you need them, no expense when you don’t
Vendor Expertise with Minimal Oversight

• Developed a more efficient and cost-effective synthesis route for an
isolated impurity
• Development and pre-packaging of solution reference standards
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Other Considerations
Successful outsourcing relationships require oversight
• Cannot initiate and then ignore
• May change depending on loss of key talent
• Selecting the low cost third party may not be beneficial in the long
run if high employee turnover is an issue
Understand the contract
• Sales staff that gain the business may have a different understanding
than the technical staff who design and implement their
products/services
• Include all required deliverables
Internal (in-sourcing) vs. external (outsourcing)
• Allows for direct oversight of contracted activities but internalizes
infrastructure costs
Thank You
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Selection of Source Material for

Reference Standard
Anu Bansal, Associate Director

Heather Runes, Sr. Technical Manager
MMTech, Pharma Technical Quality
Genentech, A Member of Roche Group
Introduction
What is a reference standard?
Reference standard (RS) is a material used to determine
presence or absence of strength, identity, purity and/or
potency of the target product.
How to choose a RS?
Target product attribute(s) and testing purpose determine the
reference standard choice
Desired RS should be sensitive and specific to ensure test
method and/or product undesired performance and/or
attribute can be detected and analyzed with high confidence
Is there only one single RS per sample/product?
Use of a single RS is ideal but more than one RS may be
necessary to determine presence or absence of target
product attributes 2
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Types of QC Reference standards
Purpose of Reference Standard in

Pharmaceutical QC
• For method development and validation and equipment
calibration
• Critical for determining strength, identity, purity, and potency
of each product lot
• Critical for:
product comparability after process changes
technology transfer
method monitoring (if used for system suitability)
training and troubleshooting
• The link throughout the product lifecycle - from the early
stage clinical trials to the commercial product
• To qualify future primary and working reference standards
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Use of reference standards in analytical

methods
For identity confirmation

For direct quantitative test sample result determination, e.g.
relative purity and potency
To generate a test sample response through the qualitative
comparison of a quality attribute e.g. purity by SDS-PAGE
or test method requiring result to be “conforms to standard”
As a component of system suitability and/or assay acceptance
criteria to demonstrate assay precision, efficiency, recovery
and resolution that is similar to historical performance
Method performance trending/monitoring programs
To directly detect a “known or stability indicating” impurity
What is required in a Reference Standard for

analytical methods?
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Reference standard requirement

At all stages, the reference standard should be ‘representative
of production and clinical materials’ (ICH Q6B).
The quality attributes of the standard should represent the
desired product characteristics
A reference standard should not demonstrate substantially
different profile than the product lots it is intended to
support release and stability testing
For a potency bioassay, the reference standard must have a
biological activity that is identical to the biological activity of
the target sample (i.e. shows parallelism)
RS should be free from assay interfering substances
The reference standard must be homogeneous and stable
Sourcing of Reference standard

Primary consideration for selecting material to be used as
reference standard is its intended use
Reference standards may be obtained from pharmacopeias
(e.g. USP and Ph. Eur.), other authorities (e.g. WHO), or
commercial suppliers (e.g. NIST, NIBSC), as available and
appropriate
An in-house primary and/or secondary reference standard is
typically manufactured using a drug substance lot(s)
representative of the existing manufacturing process. It may
be additionally purified, if necessary
Specialized excipients utilized in pharmaceutical
manufacturing may be obtained from the supplier and/or
manufacturer of the material.
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Attributes desired in a Primary and

working RS
Identity - positive
Purity – representative of the product expected purity at
release and stability
Additional purification may be necessary for chemical purity
or impurity characterization
Composition – specified major, minor or trace forms, e.g.
excipients, stabilizers, solvents
Special physico-chemical properties – concentration,
viscosity, moisture etc.
Homogeneity and stability
Generally, biological reference standards cannot be fully
characterized by physicochemical tests alone, and require
the use of specific bioassay to establish their specific
activity 9
Reference Standard requirement

(Chemical vs. Biologics)
RS attribute compared to Chemical Biologics
Target
Purity Similar or better Similar

Identity Positive Positive
Stability Better Better
Strength Similar or better Similar
Matrix Can be different Similar or Different
Activity Not necessary Similar (parallel)
Product related impurities Similar Similar
Process related impurities Similar Similar
Same process as Product Desired but not Yes
manufacturing process necessary*
Linkage to Ph III material Not necessary* Necessary

* Depends on the molecule and process, e.g. synthetic peptide vs. small molecule 10
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Sourcing: Drug Substance or Drug

Product?
For small molecules, API is used for RS.
Drug substance may be suitable for a reference standard:
1. Some drug products may not be stable enough to serve as a long
term reference standard in the final formulation
2. The formulation and/or concentration of drug substance may lend
greater stability to the molecule, such that it may be used for an
extended period of time as a reference standard
3. Drug substance may be better suited to illustrate the presence of
impurities if final product goes through additional processing steps
4. Further formulation, processing and different ratio of major and
minor forms in final drug product may not provide appropriate
sensitivity needed for testing
However, there may be the need to have both DS and DP
reference standards depending on how they are used in
assays. 11
Sourcing consideration for chemical

reference standard
A primary reference substance exhibits the highest degree of
purity which is reasonably achievable
Primary reference standard (API) is generally manufactured
according to a special synthetic process or directly from a
production API batch. It may undergo additional purification
to yield a very pure form.
Impurity reference substances (relevant synthetic precursors
and by-products, potential impurities and degradation
products) are usually obtained by selective synthesis or
isolation.
RS obtained from further purification shall be characterized
carefully as this may impact physico-chemical and/or
stability properties of the RS, e.g. X’tal properties, mass
balance etc. 12
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Purity profile for an example chemical

compound
Characterization lot 2
1 3 4
Reference lot 2
1 3 4
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Sourcing consideration for Biological RS

A primary reference standard is a material, which is the key
(gold) standard, that links commercial product to the
material utilized in pivotal clinical trials. RS represents the
desired characteristics of the production lots.
Generally, biological reference standards cannot be fully
characterized by physicochemical tests alone, and require
the use of specific quantitative bioassay (e.g. cellular,
immuno, or enzymatic) to establish their specific activity
Product potency ( through bioassay) is established relative to
RS. Therefore, it is necessary that the dose–response
characteristics of the standard are the same as those of
tests samples (parallelism)
It is critical that the RS manufacturing process be the
same/comparable as that of the production lots
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Biological RS Sourcing contd.

Bioassays are multifactorial making it difficult to quantitatively
correlate biological response to a single bio-analyte –
source of RS can impact bioassay response
RS used in quantitative assay validation is critical for method’s
specificity and product specification. Hence, link to the RS
used during pivotal clinical trial must be maintained
throughout production to prevent product drift
First primary reference standard is generally established early
or late Phase III from commercial scale material
Meeting specifications (both the test and limits) alone is often
not enough to ensure the reference standard fully
represents the product - additional characterization tests are
usually employed for the primary reference standard
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It is desired that primary standard is maintained for long-term
and reserved for future reference standard lot qualification:
as 1-2, 1-3, 1-4 and not 1-2-3-4, to ensure there is no drift
Because quantitative attributes (potency and content) are
determined by direct comparison to the reference standard,
these parameters must be precisely determined during new
reference standard qualification
Biomolecules have variable purity profile due to post-
translational modification and/or process related impurities –
extensive characterization of RS is necessary to support
product comparability, investigation etc.
Qualification tests generally include some or all of the
following: potency, concentration (strength), mass, primary,
secondary and tertiary structure, disulfide structure,
carbohydrate structure and impurity profile 16
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Bioproducts are temperature sensitive and are prone to
degradation over long-term storage. Therefore, for long term
stability it may be necessary to have RS formulation and
presentation different than that of the test article, as long as
it does not adversely affect the test method, e.g. lyophilized
RS vs. liquid product
Microbial, protein aggregation and particulate controls be
maintained during RS manufacturing to ensure long term
stability
To maintain long-term supply of the primary reference standard
it is desirable to manufacture secondary/working reference
standard lot for routine use.
Secondary RS must be qualified against the primary standard
and quantitative results must be precisely determined to
prevent drifts. 17
Effect of Process Change on profile
Lot A
Lot B
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Effect of process change on Profile
Lot A
Lot B
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Source of RS
Innovator production process or third party manufacturer?
Depends on the RS intended purpose
A new lot of RS must always be fully characterized
RS used for non-quantitative testing can be sourced from
material obtained from processes similar to innovator - as
long as impact of difference from original RS have been
established to be non-critical. Additionally, the product
released using such sourced RS do not affect product
quality and safety requirements.
RS quality and characteristics are highly critical for methods
requiring reference standard for quantitative output. In this
case, impact of differently sourced RS must be evaluated
against specific method’s performance as well as impact to
the product specification.
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Source of RS contd.
It is usually not desirable to use biological primary reference
standard obtained from a different process for product
release than the reference standard used during pivotal
clinical studies, due to biological molecules complexity and
impact to biological activity (unless equivalency for potency
has been established)
If a different sourced material is used to generate a new
biological RS lot, it is recommended:
• to be qualified against the original primary reference standard used in
pivotal clinical studies
• quantitative limits be established using the same or comparable
methods used during original primary reference standard qualification
• extensive characterization is performed to ensure the critical quality
attributes and overall quality profile is maintained
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Summary – RS Sourcing consideration

Intended purpose of RS – attributes to be measured, methods
to be utilized and analytical specification
Selection of material –appropriateness
Manufacturing process utilized – comparable to the commercial
manufacturing process
Qualification and characterization of RS – methods used and
their validity, attributes characterized through high precision
for quantitative assays, comparability to the desired product
characteristic and homogeneity
Stability on storage and distribution
Documentation and traceability
Environmental and handling control (e.g. sterility, volatility,
hygroscopic, sensitivity to temperature, air or light etc)
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Acknowledgements
Heather Runes
Dieter Schmalzing
Susan Janes
Hansjoerg Beckh
Nessie Tam
Nik Chetwyn
Michael Dong
EDQM Organizing Committee
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Compendial Reference Standards

Manufacturing
Li Bo, Ph.D.
National Institutes for Food and Drug Control, China

4 September 2012
Outline
 RS evaluation
 RS manufacturing
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Management procedures of RS
Create RS development plan
Candidates sourcing
Qualified
Subpackage
Test（including collaborating test）
Approval
Approved
Package Storage
Supply Center
National reference standard

quality management system
protocol develop (1) Fist lot approval
(1) API screening

candidates sourcing and test （2）API testing
(1)filling environment
filling （2）guidelines for filling
(1) sampling
evaluation （2）testing insturments
（3）protocol
（4）analysis report
stability testing (1) time interval
(1) approval procedures

approval （2）approval
(1) packing
packaging and store （2）storage
(1) supply
distribution （2）supply chain
(1) feedback information collect

market feedback （2）correction actions
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RS management system
The system consists of four parts :
1 Preparation management
2 Sub-package and package Management
3 Storeroom management
4 Supply management
RS management system (Cont.)
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Application form for RS candidates:

Initial forms for sub-package and package:
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Database information of RS:
Procurement
 Goal:
– To source high quality candidates that can be
used in reference standards development
 Accomplished by:
– donations
– customer syntheses
– purchases
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Procurement
Purity requirements:
1. Assay RS: not less than 99.5％

or one batch API with appropriate quality
2. Limit testing RS: not less than 90%（TLC）or 95%
（LC, etc）
3. System suitability RS: not less than 99.5％
or one batch API with appropriate quality
4. Identification RS: One batch API with appropriate
quality
Classification
1. Quantitative use
Assay standard and limit test standard, value assignment by
 Mass balance
 Microbial assay or bioassay
2. Qualitative use
Identification standard (e.g., IR)
System suitability (e.g., HPLC resolution or peak identifier)
No purity value assigned on package label
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Characterized
Structures elucidation of Chemical RS:
The first batch ：
 UV
 IR
 NMR
 MS
 Element analysis
 X－ray
 Function group analysis
Characterized (Cont.)
Purity test of Chemical RS:
 HPLC (DAD)
 GC
 TLC
 CE
 DSC
 Compatibility degree method
 UV, IR, NMR
 Titration
 Optical activity
 Water, residual solvent, loss on drying
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Collaborating study
1. Protocol prepared by NIFDC laboratory.

2. Protocol and samples sent to participants.
3. Participants test and feedback results.
4. Results evaluated by NIFDC.
5. Report with proposed assigned value .
6. Approval from expert committee.
7. Adoption by the commission.
Collaborating study (Cont.)
Selection of collaborating test lab from:
1. Local drug control institutes

2. Manufactures
3. NIFDC
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Chemical RS value assign
Mass balance (majority of the

small molecules, some biologics):
X（%）=（100.0 –water/solvent–residual
on ignition） x chromatograic purity/100
Production technologies
Powder filling
Liquid Filling
Freeze drying
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Production conditions
1. Highly toxic / highly potent substances:

glove box under negative pressure for
containment and protection of the operators
2. Hygroscopic substances:
controlled humidity
3. Substances sensitive to oxidation:
under inert gas
Label
Institute emblem
Bar code
Only one number
Continuation
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Label (Cont.)
RS value:
 No labeling value, account for 100.0％, or
 Have labeling value, base on below using instruction:
– Do not dry before using, take the labeling value.
– Need dry before using, the labeling value is after drying
value.
– Determine the water content before using, the labeling
value should be subtract by the water content.
 There are no labeling value for RS intended for
identification and impurities testing.
Label (Cont.)
RS value:
1. Assay RS: XX.X% 100.0%
2. Limit testing RS: If purity is higher than 95.0% ,
account for 100%；If lower than 95.0%，account for
labeling value
3. System suitability RS: No labeling value
4. Identification RS: No labeling value
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Package
Supply chain
1. Supply principals：on-demand supply

2. Supply mode：two level supply chain
 The first level：NIFDC
 The second level：local drug control institutes
3. Supply management：Dynamic management
The second level is audited and assessed by NIFDC
every year
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Supply chain (Cont.)
 NIFDC provides RS to the second level unit.

 Both the two level units can directly supply local drug
control institutes, drug manufacturers and related
research institutes and other end-user of RS.
Supply chain (Cont.)

 Self pick up and mailing.
 For large amount, the second level unit must check
in NIFDC.
 Regard with toxic, narcotic, psychotropic,
radioactive, and pathogenic microorganisms RS, self
pick is mandatory with the official documents.
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Monitoring programme
Once established, the RS is underwent periodic testing to

ensure its suitability for continue use.
Testing interval and extent depends on the usage of the
RS and its stability information available.
In general the major concern is focusing on the
properties that may change during the life cycle of a RS.
No expiry date is provided.
Question?
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Storage and Distribution of

Pharmaceutical Reference Standards
INTERNATIONAL SYMPOSIUM ‘PHARMACEUTICAL REFERENCE STANDARDS’
3‐4 SEPTEMBER 2012, STRASBOURG, FRANCE
Robert L. Watters, Jr Andrea Iwanik
Associate Director for Measurement Services Director, Reference Standards
Production
Mark Cronise
Supervisory Physical Science Technician Sarah Koegel
Manager, Reference Standards
Production
Ilse Bercik
Physical Scientist
National Institute of Standards and Technology United States Pharmacopeia
Three Challenges
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Reference Materials
NIST SRMs and RMs USP RSs
• A CRM that meets additional • A highly characterized
NIST-specific certification specimen of a drug
criteria substance, excipient, major
• Certificate reports the results impurity, degradation
of characterizations (value product,
assignments and uncertainties) food ingredient, or
• Uses performance calibrator
– to help develop accurate
methods of analysis • Uses
– to calibrate measurement – in compendial methods
instruments – to assure that products are
– to ensure the long-term of the appropriate identity,
adequacy and integrity of strength, quality, and purity
measurement quality assurance
programs
– as a convenience to industry
Reference Materials (2)

• NIST RMs and SRMs • USP RSs and CRMs
– 1209 SRMs – 4 CRMs
– 86 RMs – 2929 RSs
– 32K units/yr. – 500K units/yr.
– Categories – Categories
• Environmental • Health and Clinical
• Industrial
• Health & Clinical
• Engineering
• High-Purity
• Physical Properties
• Food & Agricultural
• Radioactivity
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Global Reach
NIST SRMs USP RSs
Global Reach Consequences (1)
• Shipping/Carrier complications
– Carrier policies
• Can change monthly
– Customer preferences
– Government procurement barriers (NIST problem)
– Carrier capabilities
• Advertised vs. our experience
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• Customs issues
– Harmonized Commodity Description and Coding
System (HS) established a tariff code 3822.00 for
CRMs– Free
• Varying interpretations resulting in costs to customers
– Lack of required storage facilities
– Local “customs” that increase costs to customers
• Other country‐specific issues
– Manufacturer’s declaration
– Health certificate for human or animal‐derived
materials
– Customized labelling
• USP shipping system
– Shipping name
– UN number
– Hazard class
– Handling, packaging & labelling instructions
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Cold Storage
• NIST
– 24 000 units in 2003
– 55 773 units in stock (7 %)
• USP
– ~1.2 M units (56 %)
Cold Storage Facilities
• NIST – new warehouse 2167 m2
– 125 m3 at 4 °C
– 200 m3 at ‐20 °C
– 200 m3 at ‐75 °C
• USP
 17 refrigerators
 7 freezers
 833 m3 total
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Hazard Assessment
• Safety Data Sheet (SDS)
• Labelling
• Work process flow
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2012 OSHA GHS Hazard Communication
• Safety Data Sheet (SDS)
– 16 Sections
• Section 2: has changed to incorporate pictograms and
Hazard or Precautionary Statements; it requires calculations
and specific information such as pH and toxicity to be able to
classify pure chemicals and mixtures
• Section 9: Minimum required information for
Physical/Chemical properties
• Section 12: Ecological information non‐mandatory in the US
• Labels
– Labels are required to include warnings, pictograms,
Material Measurement Laboratory
hazard/precautionary statements
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Calculations Needed
• Health Hazard • Environmental Hazard
– Acute Toxicity – Hazardous to the Aquatic
– Skin Corrosion/irritation Environment
– Serious Eye Damage/Eye • Acute/Chronic
Irritation • Bioaccumulation
• Degradability
– Respiratory or Skin
Sensitization
– Germ Cell Mutagenicity • Physical Hazard
– Carcinogenicity – Explosives
– Reproductive Toxicology – Flammables
– Target Organ- Single Exposure – Oxidizing
– Target Organ-Repeated – Self Reactive
Exposure – Pyrophoric Solids/Liquids
– Aspiration Toxicity – Self-Heating
– Organic Peroxides
– Corrosive to Metals
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Challenges of Mixture Classification:

Acute Toxicity Example
100 100 ∑ 10%

or
Category 1 Category 2 Category 3 Category 4

Exposure route
Oral (mg/kg bodyweight) ≤5 >5 and ≤ 50 >50 and ≤ 300 >300 and ≤ 2000
Dermal (mg/kg bodyweight) ≤5 >50 and ≤ 200 >200 and ≤ 1000 >1000 and ≤ 2000
Inhalation - Gases (ppm)

≤ 100 >100 and ≤ 500 >500 and ≤ 2500 >2500 and ≤ 20000
Inhalation - Vapors (mg/l) ≤ 0.5 >0.5 and ≤ 2.0 Material Measurement Laboratory

>2.0 and ≤ 10.0 >10.0 and ≤ 20.0
Inhalation ≤ 0.05 >0.05 and ≤ 0.5 >0.5 and ≤ 1.0 >1.0 and ≤ 5.0
Dusts and Mists (mg/l)
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OSHA new GHS SDS
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OSHA: New GHS Label
Information on Label and SDS Match
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Section 9: OSHA Required

Information
• Appearance (physical • Upper/lower flammability
state, color, etc) or Explosive limits
• Odor • Vapor pressure
• Odor threshold • Vapor density
• pH • Relative density
• Melting point/Freezing • Solubility (ies)
point • Partition coefficient:
• Initial boiling point and n-octanol/water
boiling range • Auto-ignition temperature
• Flash point • Decomposition
• Evaporation Rate Temperature
• Flammability (solid, gas) • Viscosity
All items are required; if not applicable or not available: it has to be indicated
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Information Needed Safety Data Sheet,

Label, and Department of Transportation
8 properties are needed for classification
Needed
Most
•Appearance (physical state, color, etc.)
•Upper/lower flammability or explosive limits
•pH
•Initial boiling point and boiling range
•Flash point
•Flammability (solid, gas) Material Measurement Laboratory
•Auto‐ignition temperature
•Melting point/freezing point
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Safety Data Sheet and Label
Classification
Figure A.1.1: Tiered approach to classification of mixtures for acute toxicity

Test data on the mixture as a whole

No Yes

Sufficient data available on Yes
similar mixtures to estimate Apply bridging principles in A.1.3.5 CLASSIFY
classification hazards

No

Available data for all Yes
Apply formula in A.1.3.6.1 CLASSIFY
ingredients

No

Other data available to Yes
estimate conversion values Apply formula in A.1.3.6.1 CLASSIFY
for classification

No

Apply formula in A.1.3.6.1 (unknown

Convey hazards of the ingredients ≤ 10%) or
CLASSIFY
known ingredients Apply formula in A.1.3.6.2.3 (unknown
ingredients > 10%)
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OSHA 2012 HazCom Effective Dates

Effective Completion Date Requirement(s) Who
December 1, 2013 Train employees on the new label elements and safety Employers
data sheet (SDS) format.
June 1, 2015* Compliance with all modified provisions of this final Chemical manufacturers,
December 1, 2015 rule, except: importers, distributors and
The Distributor shall not ship containers labeled by employers
the chemical manufacturer or importer unless it is a
GHS label
June 1, 2016 Update alternative workplace labeling and hazard Employers

communication program as necessary, and provide
additional employee training for newly identified
physical or health hazards.
Transition Period to the effective May comply with either 29 CFR 1910.1200 (the final Chemical manufacturers,
completion dates noted above standard), or the current standard, or both importers, distributors, and
employers
* This date coincides with the European Union implementation date for classification of mixtures.
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Current Process
Material received
Processing/packaging
Characterization
Statistical analysis
Technical reports
Hazard assessment
Certificate, labels, & SDS
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New Process
Material received
HA, SDS & label
Processing/packaging
Characterization
Statistical analysis
Technical reports
Certificate & labeling
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04/09/2012
Receiving Candidate Material from a
Supplier
• Concerns about having a non‐compliant label
• Special Concerns with SRMs that need to be
frozen and having to do relabeling
23
12

Reference Standards

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Reference Standards

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PHARMACEUTICAL REFERENCE

11th International Symposium

3-4 September 2012, Strasbourg, France

Session 3 – Presentations (Part 1)

Material Management / Technology

Managing Third Parties for the Preparation

Deciding What to Outsource

Missing or unique technical capabilities

Operations that have minimal oversight requirements

Well defined processes with minimal associated

Processes that are performed infrequently or require

Always keeping in mind cost and quality

Expertise and Customer Service

Examples of Outsourced Operations

Prepackaging and labeling of bulk material

Special synthesis of small molecules

Disaster recovery storage

Physicochemical characterization tests (where site

Examples of Outsourced Operations

Processing and dispensing of routine customer orders

Shipping dock services

Remote distribution centers

The level of third party oversight

High Level Oversight Considerations

In-depth and higher frequency audits

Detailed master service agreement

Detailed performance metrics monitored

“Man in plant” for key operations

The key to a successful third party relationship

Specifically, the third party should understand

High Level Differences

Reference Standard Drug Substance or Drug Product

Intended use – laboratory control Intended use – human dosing

Real Examples: Problems when

Critical raw material requirements not identified

Real Examples: Problems when

Quality and Expertise

Real Examples: Benefits when

Real Examples: Benefits when

Vendor Expertise with Minimal Oversight

Selection of Source Material for

Anu Bansal, Associate Director

Types of QC Reference standards

Purpose of Reference Standard in

Use of reference standards in analytical

For identity confirmation

What is required in a Reference Standard for

Reference standard requirement

Sourcing of Reference standard

Attributes desired in a Primary and

Reference Standard requirement

Purity Similar or better Similar

Linkage to Ph III material Not necessary* Necessary

Sourcing: Drug Substance or Drug

Sourcing consideration for chemical

Purity profile for an example chemical

Sourcing consideration for Biological RS

Biological RS Sourcing contd.

Biological RS Sourcing contd.

Biological RS Sourcing contd.

Effect of Process Change on profile

Effect of process change on Profile

Summary – RS Sourcing consideration