Product Release Process

Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group

Life Sciences Innovation Forum - Regulatory Harmonization Steering Committee (LSIF-RHSC)

 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Principles
Manufacturers are required to ensure that the quality
of product released is appropriate
• Take into account
– The regulatory requirements including GMPs for release in the
country in which the manufacturer operates and, if exported, the
destination company’s and regulatory requirements
– The requirements of the relevant marketing authorisation or
analogous instrument such as Drug Master File or CEP
– The requirements of the customer as defined in written
agreements, if applicable
– Storage and transportation requirements, where appropriate

These should be primarily met by the diligent application

of GMP throughout a company’s operations
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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Implementation Of These Principles

• Principles are intended to be met
– Through checks at the product release stage
– By the diligent application of GMP throughout a company’s
operations
• Quality must be built into operations through sound
– Facility and process design
– Suitable equipment and raw materials
– Trained personnel
– Controls
– A range of other measures to ensure robust production.
• Checks at release serve only to provide final verification
Manufacturers ensure appropriate quality of product released
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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Elements of Appropriate Quality

In-process testing End product testing

(e.g. IPCs, process monitoring,) (e.g. specification, stability, comparability)

Product Release
Production Process

Decsion
Input controls
(raw materials and with process understanding
components)
and continual improvement

Procedural controls
(e.g. process design, facility, equipment and operational controls
incl. people management, training, SOP’s etc.)

Processes should be carefully evaluated for reproducibility

at launch stage, and state of control should
be further assessed on an ongoing basis
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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Product Release Decision

Compliance with Compliance with

GMP Marketing authorisation

The person, who decide, is accountable for adhering to compliance

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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Product Release Decision

Several elements should be considered
Product Facility / Process System
Product Manufacturing Quality
Registration System
(CMC) & Distribution (GMP-GDP)

Quality Culture &

Regulatory Compliance Oversight Regulatory
Assessment Inspections

A sound process Site / Culture Suitable equipment

design and raw material
Controls and a range
Trained personnel
of other measures
Quality = Product + Process + System + Site / Culture
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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Considerations for Product Release

• Manufacturing should have followed defined procedures
– Some elements of the product release process are defined
and proposed in the marketing authorization dossier and
agreed to by the regulators
• Product-related data from each individual batch should
be assessed
– Trends of critical parameters and attributes can be evaluated
in the context with other batches manufactured

GMPs applied and handled under a Quality System

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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Considerations for Product Release

• Environmental, facility, utilities and equipment
• There is an increased focus on trending and process
monitoring
– On-line, in-line, at-line testing can lead to continuous
process verification.
• Corrective Action and Preventive Action (CAPA) caused
by batch related non conformance events closed out
prior to release
– Any deviation or atypical event that occurs during
manufacturing (e.g., involving the manufacturing process,
facility, personnel, testing) is recorded and assessed

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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Considerations for Product Release

• To release a batch all specifications must be met
– Out of specifications should be investigated prior to a
potential release
Certificate of Analysis
• A Certificate of Analysis (CoA) can be issued
– Includes results from end product testing
– In compliance with the specification as part of the
release decision
– In compliance with the filing commitments
See: Internationally harmonised requirements for batch Certification, EMA; EMA/INS/MRA/387218/2011 Rev 5, June 2011
http://ec.europa.eu/health/files/eudralex/vol-4/mra_batch-certificate_05-2011.pdf

• Audits can evaluate performance

– A given batch has been made under the proper conditions and
practices (e.g. documentation, adherents to batch record and
cleaning procedures)
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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Principles (Example: GMP for APIs)

• No materials should be released or used before the
satisfactory completion of evaluation by the quality unit(s)
unless there are appropriate systems in place to allow for
such use
– e.g. release under quarantine or the use of raw materials or
intermediates pending completion of evaluation
• APIs and intermediates should only be released for
distribution to third parties after they have been released
by the quality unit(s).
– APIs and intermediates can be transferred under quarantine
to another unit under the company’s control when authorized
by the quality unit(s) and if appropriate controls and
documentation are in place ICH Q7, chapter 2.17, 10.20
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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Regulatory Environment
• Regulations require for some one, who releases the
product, have to have an appropriate qualification
• The approving a product for release, as described, is
understood as approval by the actual manufacturer of a
product
• Regional / domestic regulatory licensing procedures can
require a additional approval as part of the product
release processes for a specific market
• The concept of a ‘responsible person’
can be applied

Opportunities to support harmonization

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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Concept, That Can Be Applied for Drug Product

‘Responsible Person’ according to PIC/S guidance and many related countries
also named: ‘Authorized person’ (WHO), ‘Qualified person’ (EU)

• Can be a person recognized by the national authorities

– Having the responsibility for ensuring that each batch of finished product
has been manufactured, tested and approved for release in compliance
with the laws and regulations in force in that country

• Pharmaceutical products are not sold or supplied before a

responsible person has certified
– No batch of product is to be released for sale or supply prior to certification
by the authorized person(s). In certain countries, by law, the product
release is a task of the authorized person from production together with the
authorized person from QC.
– Each production batch has been produced and controlled in accordance
with GMP and the requirements of the marketing authorization
– Any other regulations relevant to the production, control and release of
pharmaceutical products
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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Diversion of Material to Alternative Markets

Manufacturers may be tempted to divert the material in question
to a market or customer with less demanding standards

• Root cause: product fails to meet specific domestic /

regional requirements e.g.
– Specifications or other requirements
– Pharmacopoeial standard or
– Customer requirements
• Firms should understand and follow principles in these
globally harmonized standards e.g.
– International Conference on Harmonisation (ICH)
– Pharmaceutical Inspection Cooperation Scheme (PIC/S)
– Pharmacopoeia harmonisation process
APEC economies should drive to support harmonization
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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Diversion of Material to Alternative Markets

Essential problems to be considered
• A failure will likely continue to happen appears, when
differences in expectations and standards exist
– It is inappropriate to disregard this as of no consequence because
the requirements of the alternative market are seemingly met
– The fact that something has gone wrong increases the risk of
substandard product being supplied to the alternative market
– It is acknowledged that there are occasions where the
manufacturer is able to adequately justify switching to an
alternative market with different requirements
– When a robust science and risk-based investigation concludes that
product quality is not adversely affected

There is no place for divergent quality standards in a global market

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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Considerations - Summary
Approving a product for release should always ensure
• Marketing and manufacturing authorizations for the product have been
met
• The principal manufacturing and testing processes have been validated
• All the necessary checks and tests have been performed and account
taken of the production conditions and manufacturing records
• All necessary production and QC documentation has been completed
and endorsed by supervisors trained in appropriate disciplines
• Any planned or unplanned changes or deviations in manufacturing or
QC have been notified in accordance with a well-defined reporting and
investigation system before any product is released. Such changes may
need notification to, and approval by, the medicines regulatory authority
• Audits, as appropriate, self-inspections and spot-checks are carried out
by experienced and trained staffBased on e.g. WHO Technical Report Series 986, Annex 2, 2014
The principles and guidelines of GMP have been followed
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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Key Message
• Manufacturers are required to ensure appropriate quality of
product released
– Primarily met by the diligent application of GMP throughout a
company’s operations
– Corrective Action and Preventive Action (CAPA) caused by batch
related non conformance events closed out prior to release
• Checks at release serve only to provide final verification
– Control of product, manufacturing processes (regulatory
compliance), systems are in place at the site level
– A product release process should be followed

Note: There are regional differences in the regulation of product release

across countries and the manufacturing licensing procedure as of today
Expectations are similar: Therefor harmonization of requirements
and implementation should be supported by APEC economies
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 Roadmap for Global Medical Product Integrity and Supply Chain Security
Manufacturing Practices Work Group:
PRODUCT RELEASE PROCESS

Conclusion
The product release decision is a holistic decision,
that considers all available information
on the performance of the operation
during a given cycle of manufacture
to arrive at a final disposition

Release
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