APEC AHC – USP Center of Excellence (CoE) for Product Quality & Supply Chain

Pilot Program: “Securing Medical Product Quality Through the Supply Chain”

Incoming Materials Check

Ong Kang Teng

Health Sciences Authority of Singapore
28 March 2017
Licensed &
inspected for
compliance
to local
regulation &
standards
DEG Contamination

US FDA presentation by Edwin Rivera-Martinez, June 2010

Formulation of Acetaminophen cough Syrup

Active
Ingredient

Excipients
If you are a Acetaminophen Syrup Manufacturer

Source for Registration of

starting starting
materials
• Acceptable materials &
quality product
• Specification
attributes
• Analytical
• Approved
method
supplier
Validation
• Contract
• Approved
agreement
Supplier
• Process
validation
ICH Q6A
Specifications:
Test Procedures
and Acceptance
Criteria

Specification of
Paracetamol EP

 Description
Identification
 Test for
impurities
(related
substances,
residual
solvents)
 Assay
If you are a Acetaminophen Syrup Manufacturer

Source for
starting
materials
Registration GMP
of starting Control
materials &
product

• Specification • Correct starting

• Analytical materials used
• Acceptable method –Identity,
quality Validation Quality &
attributes • Approved Supply chain
• Approved Supplier • Appropriate
supplier • Process handling
• Contract validation
agreement
Management of Changes in the Starting Materials Supply
Chain throughout the Product Life Cycle

Risk
Assessment

Validation

Approval
If you are a Acetaminophen Syrup Manufacturer

Source for
excipient

Registration GMP
of excipient Control

• Specification • Correct starting

• Analytical materials used
• Acceptable method –Identity,
quality Validation? Quality &
attributes • Approved Supply chain
• Approved Supplier? • Appropriate
supplier • Process handling
• Contract validation?
agreement?
• Regulatory approval is
usually simplified for
compendial excipients
• For a noncompendial
excipient, updates and a full
description of the
characterization,
manufacture, control,
analytical procedures, and
acceptance criteria should
be provided in an information
amendment.
If you are a Acetaminophen Syrup Manufacturer

Source for
excipient

Registration GMP
of excipient Control

• Specification • Correct starting

• Analytical materials used
• Acceptable method –Identity,
quality Validation? Quality &
attributes • Approved Supply chain
• Approved Supplier? • Appropriate
supplier • Process handling
• Contract validation?
agreement?
Checking of Incoming Goods
A simplified process Name of Material
Internal Code
Batch No.

1. Receipt Status QUARANTINE

Expiry Date Date Received

2. Identification Date Signature

Name of Material
3. Quarantine Internal Code

Batch No.

4. Sampling and Testing for Release Status RELEASED

Expiry Date Retest Date

5. Approve for further use Date Signature

Name of Material

Prerequisites e.g. Internal Code

Batch No.
– Written Procedures Status REJECTED
– Designated Areas Expiry Date

Date Signature

– Supplier Qualification, if appropriate Name of Material

Internal Code

Batch No.

Checking is the last line of defense HOLD

Status

Expiry Date Retest Date

for medical product integrity Date Signature

How do you verify
the correct supply chain for each starting material?

• For each delivery, the containers

should be checked for integrity of
package and seal and for
correspondence between the delivery
note and the supplier's labels.
• Approved Suppliers list
Name of Material
Internal Code
Batch No /
Receiving No.
Quarantine / Release /
Status
Rejected / Hold ( Use Color)
Expiry Date Retest Date
Receiving Date Signature
How do you verify the
correct supply chain for each starting material?
How do you verify the correct identity and
quality of the starting materials?
There should be
appropriate
procedures or
measures
to assure the identity of the contents
of each container of starting
material.

 Is checking the CoA given

by supplier sufficient?
How do you verify the correct identity and
quality of the starting materials?
How do you verify the correct identity and quality
of the starting materials?
How do you verify the correct identity and quality
of the starting materials?
• The identity of a complete batch of starting materials
can normally only be ensured if individual samples
are taken from all the containers and an identity
test performed on each sample.
• The quality of a batch of starting materials may be
assessed by taking and testing a representative
sample.
How do you verify the correct identity of
Glycerin?

The Agency recommends that:

 Drug product manufacturers
perform a specific identity
test that includes a limit test
for DEG on all containers of all
lots of glycerin before the
glycerin is used in the
manufacture or preparation of
drug products because of the
serious hazard associated with
DEG contamination.
Specific Identification Test for Glycerin

Identification
of Glycerin by
Infrared
Absorption
Spectroscopy

https://www.perkinelmer.com/lab-
solutions/resources/docs/APP_Detection_Adulteration_Glycerol_DiethyleneGlycol_IR.pdf
Specific Identification Test for Glycerin

Gas
Chromatography
assay method
which can detect
0.1% DEG.

K. MOLEVER, J. Cosmet. Sci., 61, 225–234 (May/June 2010). Simplified assay of diethylene glycol and ethylene glycol in
various raw materials by capillary gas chromatography
http://journal.scconline.org/pdf/cc2010/cc061n03/p00225-p00234.pdf
Specifications for
starting and packaging materials

a) A description of the materials, including:

- The designated name and the internal code reference;
- The reference, if any, to a pharmacopoeial monograph;
- The approved suppliers and, if reasonable, the original
producer of the material;
- A specimen of printed materials;
b) Directions for sampling and testing;
c) Qualitative and quantitative requirements with
acceptance limits;
d) Storage conditions and precautions;
e) The maximum period of storage before re-
examination.
Sampling Procedure for Starting Materials

Sampling should be conducted in such a way to

prevent cross contamination.
Sampling Procedure for Starting Materials

• Method of sampling;
• Equipment to be used;
• Amount of the sample to be taken;
• Instructions for any required sub-division
of the sample;
• Type and condition of the sample
container to be used;
• Identification of containers sampled; 1 of 12
Sample has
• Any special precautions to be observed, been taken
especially with regard to the sampling of by QC
Nina
sterile or noxious materials;
• Storage conditions;
• Instructions for the cleaning and storage
of sampling equipment.

25
How many containers should be sampled for identity
& quality control test?

The identity of a complete batch of starting materials can

normally only be ensured if individual samples are taken
from all the containers and an identity test performed on
each sample.

It is permissible to sample only a

proportion of the containers where a
validated procedure has been
established to ensure that no single
container of starting material will be
incorrectly identified on its label.

Annex 8, clause 2
How do you verify
the identity and quality of the starting materials?

Under certain arrangements, it is possible that a validated

procedure exempting identity testing of each incoming container
of starting material could be accepted for:

 starting materials coming from a

single product manufacturer or plant;
 starting materials coming directly
from a manufacturer or in the
manufacturer's sealed container
where there is a history of reliability
and regular audits of the
manufacturer's Quality Assurance
system are conducted by the
purchaser (the manufacturer of the
medicinal products or by an officially
accredited body.
Annex 8 of the GMP provides for derogations from the requirement for identity
testing of every container where there is a validated supply chain. Can I use
this derogation for the glycerol I purchase?

It is improbable that a procedure could be satisfactorily

validated for:
– starting materials supplied by intermediaries such as brokers
where the source of manufacture is unknown or not audited;
– Starting materials for use in parenteral products.

“Glycerol is a commercial article

that is widely used in the food and
other industries. Generally
speaking, the supply chain for
glycerol tends to be complex and
lengthy. The involvement of brokers
is common in the supply chain.’’
Evaluate the Risks
in the Starting Materials Supply Chain
Starting Materials
Manufacturers

High Risk of Distributor

Fraudulent
practice, Broker Low Risk
Repackaging, Trader
Relabeling,
Mix-up Agent

Drug Product
Manufacturer
Application of Quality Risk Management in
Materials Management
Assessment and evaluation of all
the suppliers involved in the
supply chain of starting materials
 Taking into consideration the
nature of the starting material
and the medicinal products in
which it will be used
 Complexity of the supply
chain
 Determine the extent of
evaluation & monitoring of the
suppliers (e.g., auditing,
supplier quality agreements)
 Extent of QC testing
Checking of Incoming Goods
Key Messages
• Incoming Materials Checking is critical to prevent
adulterated or contaminated materials from
entering a pharmaceutical facility.
• Personnel need to be trained on appropriate
procedures designed to prevent acceptance and
use of materials lacking integrity.
• This check is meant to detect both inadvertent
errors and willful adulteration of incoming
materials.
• Incoming material must be verified to be the
correct material of the specified quality before it
can be released to be used in pharmaceutical
manufacturing

Checking is the last line of defense for medicinal product integrity

Acknowledgement

APEC GMP Workgroup Members in 2015

• David Cockburn, EMA • Stephan Rönninger, Amgen
• Jean Poulos, Aceto • Rick Friedman, US-FDA
• Betsy Fritschel, J&J • Karen Takahashi, US-FDA
• Cindy Huang, Taiwan FDA • Kang Teng Ong, HSA
 Executive Management Responsibility:
Establish and Maintain a Robust Quality
System
• Management commitment to continual improvement and to
surfacing emerging issues
• Quality policy & planning

• Resource management

• Internal communication

• Extends in some ways beyond local site or corporation.

Also includes management review and control of....
• Outsourced activities
• Quality of incoming materials: changes in raw
material and/or suppliers 34 34
 The Global Supply Chain:
Regulatory Requirements for Chain “Links”

All parties who manufacture (includes testing), process, pack,

or hold an ingredient or drug product are responsible for
meeting CGMPs.

Adulterated Ingredient = Adulterated Drug Product

35
ICH Q10 Pharmaceutical Quality System

Pharmaceutical Technology Commercial

Discontinuation
Development Transfer Manufacturing

Investigational products
GMP

Management Responsibilities

Process Performance & Product Quality Monitoring System

PQS Corrective Action / Preventive Action (CAPA) System
elements Change Management System
Management Review

Knowledge Management
Enablers
Quality Risk Management

36
Expectations and
Recommendations
• QA as part of a larger outsourcing risk management plan
– Say what you do, do what you say, prove it, improve it
– Deming
• Tools:
– Risk Management Strategy
– Process Maps
– Supplier Quality Questionnaire
– Communications Infrastructure
– Audit Program
– Quality Agreements
– Metrics/Analytics Program
– Report cards
Industry: Traditional Quality System
Vulnerabilities (e.g.)

1. Lack of traceability
2. High complexity due to increased brokerage and trade activity
• Many suppliers are solely distributors. To protect their enterprise, the COA is
often altered to remove true identity of the manufacturer

3. Ingredient may be repackaged or relabeled multiple times

4. COAs: Original manufacturer COA not always obtained. Also,
overreliance on COA and frequently non-specific ID test on
composite sample.
5. Supplier Management: qualification programs, quality
agreements, and lifecycle monitoring are often deficient
6. Distant manufacturing sites can include special risks
• not audited by drug product manufacturer, FDA inspection may be
infrequent, and/or not subject to inspection by the regional authority

38
Quality System is the Backbone for
Ingredient Safety and Manufacturing
Reliability

• Selecting an Ingredient Supplier or

CMO
• Is the Drug Product Manufacturer’s quality system competent to
source from capable ingredient manufacturers or CMOs?
• Does price often drive decisions with minimal consideration of
the manufacturing & quality standards of the manufacturer of the
ingredient?
• Are good practices in place for identifying suppliers and
monitoring them?
• Are DP manufacturers vigilant to risks as they emerge
throughout the lifecycle?
39
Quality Unit Role
Preventing DEG Contamination in Glycerin
Drug product manufacturer Quality Unit should ensure they (e.g.):
• know the supply chain for glycerin including the component
manufacturer and any distributors.

• take precautions to identify reliable suppliers and to secure shipment

for components, to prevent DEG contamination

• test glycerin for DEG is performed on each batch

• make personnel are aware of the importance of testing and the

potential hazards if testing is not done.

• Determine identity and suitability of any repackers, and others who

distribute and prepare glycerin for their drug products, and mandate
that they routinely test all glycerin lots
Contract Manufacturing Complexities

- Quality agreements define

expectations and responsibilities
in a contract manufacturing
arrangement up front.
- Both the CMO and Product
Owner are responsible to ensure
safe products