BPS4102 Pharmaceuticals: Federal

and International Regulation

Lot Release for Schedule D biologics
 Definition of Lot Release
• A system of approval given by the National
Control Authority (NCA) for the release onto
the national market of a specific lot of
biological product based upon certification
that the lot meets appropriate in process
controls and control tests on final products
 Definition of Lot release cont’d
• Controls to be applied to the release of
batches of the product have been decided by
the NCA at the time of licensing of the
biological product
• Certification on an individual lot basis is
necessary because of the difficulty of
controlling the starting materials and
ensuring that batch to batch variation is
within acceptable limits
 Essentials of a Lot Release System

1. statutory empowerment for lot release

2. responsible organization for lot release
3. guidelines for registration for lot release
4. procedures for receipt and review of protocols and
receipt and review of testing of samples where
appropriate
5. protocol review
6. laboratory evaluation
7. lot release certificate of approval/disapproval
8. trend analysis of lot release data- protocol and/or
laboratory test
Legislation/Statutory
It is the responsibility of the National Control Authority (NCA) to
assure that biologics intended for use in its country are of adequate
quality, safety and efficacy

This is accomplished by granting of a license for a biological product

(marketing approval) and by continued monitoring after approval (lot
release, ADR reporting)

The NCA should have the authority to demand appropriate samples

(starting materials, intermediate products and finished products)

These responsibilities should have a firm statutory basis backed

by legislation as in the US Code of Federal Regulations (610) or
in the Canada Food & Drug Act and Regulations
 Model Legislation - Canada
• Division 8 of the Food and Drug Regulations list
requirements for new drugs
• Division 4 of the Food and Drug Regulations list
requirements for licensed biologics
• C.04.015 “Upon written request from the Director, a
manufacturer shall submit protocols or tests
together with samples of any lot of any drug prior to
its being sold, and no person shall sell any lot of
which the protocol or sample fails to meet the
requirements of these regulations”
Protocol Review.
lot release should be based at minimum on review of
the manufacturer’s protocol
the NCA decides what controls are to be applied to
release of batches of a product at the time of product
licensing
 Protocol Review
• the information provided by the manufacturer
should make it possible to review the manufacturing
and testing of each batch of a particular product,
including all required in-process controls and
control tests on final product to confirm compliance
with the approved specifications.
• summary protocol review report signed by expert
reviewer
• WHO model Summary Lot Protocols describe the
product process in detail.
 Protocol Review-requires appropriate
specific biological expertise
• understand the critical steps of the
production process
• know what are the critical tests to be done at
the different stages (in-process ,
intermediates, bulk and final container)
• to confirm that the information provided is
compliant with that licensed
WHO Summary Protocol for Vaccines
Summary Information on Final Lot
• lot #
• filling date
• dose
• expiry date
Detailed Information on
Manufacture and Control
 Strain
• Identity

• reference # of seed lot

• date of reconstitution of ampoule

Single harvests used for preparing
the bulk intermediate
• list of single harvests
• medium
• dates of inoculation
• temperature of incubation
• dates of harvest
• volumes
• results of in-process tests
• method of inactivation
• yield
 Bulk Intermediate
• reference #
• volume
• Tests
-details describing test
-dates
-specifications
-results
 Final Bulk & Final Product
• identification
• volume
• Tests
-details describing test
-dates
-specifications
-results
 Certification by the manufacturer

• certification by person from the control

laboratory of the manufacturing company
responsible for the production and control of
the vaccine
-type of product , lot #
-signature, name typed, date
Certification by the National
Control Authority

Canadian Lot Release System

 Factors Considered in Lot Release
• Lot release should be based at minimum on
review of lot protocols which describe the
production process in detail

• The degree to which a biologic is evaluated

by laboratory analysis (testing) can be linked
to the use of the product , the complexity of
the product, the manufacturing process and
the testing of the product
 Product Indication
• A risk benefit use of the product determines
need for evaluation and laboratory
assessment. For products such as vaccines
given to healthy individuals, the acceptable
risk is less than that for a product used to
treat an individual with a life threatening
disease.
Product Indication: factors that affect need for
evaluation and laboratory assessment

• disease state being treated (life threatening,

acute , chronic)
• age of target population (infants , seniors)
• patient type (healthy, incurable)
• population size (limited or widespread use)
• duration of treatment (short or long term)
• objective (treatment vs prevention vs
replacement vs diagnostic)
 Well Characterized Products
• complex products or products of a complex
manufacturing process require more scrutiny
than products that may be well characterized
by physical-chemical techniques.
Examples of well characterized products:
• therapeutic DNA plasmid products
• therapeutic synthetic peptide products of 40 or fewer amino
acids
• monoclonal antibodies for in vivo use
• therapeutic recombinant DNA-derived products
 Product Failures
• information on production lot failures is used
as part of the ongoing monitoring process.
• provides an indication of whether the
manufacturer has a record of satisfactory
and consistent production
 Re-processed Lots
• provides an indication of whether the
manufacturer has a record of satisfactory and
consistent production
• conditions for reprocessing must be approved
by the licensing authority.
 Inspection History

• production and testing history may be

obtained through inspection
• access to inspection reports from other
regulatory authorities
 Testing History
• invalidity test rates
• test failure rates; number of repeat tests to
give an acceptable result.
 Categorization of Products for Lot
Release
• Group1, 1A
• Group 2
• Group 3
• Group 4
 Categorization of Products for
Lot Release Group 1, 1A
• Group 1- Investigational (clinical lots)
1a- Consistency Lots (NDS,SNDS)
– written approval of vaccines for clinical trials in
the form of a release letter based upon protocol
review/testing
Categorization of Products for Lot
Release Group 1, 1A
– Pre-NOC evaluation of test methods and
specifications; conduct repeat or additional tests
on samples of the ingredients, intermediates and
final product
 Categorization of Products for Lot
Release Group 2
• post licensure-approval based on targeted
testing and protocol review
• written approval for the sale of each lot in
Canada in the form of a release letter
 Categorization of Products for Lot
Release Group 2
• protocol review and targeted testing of
samples of each lot
• some low risk products may never be put in
this group after NOC; some high risk products
may stay in this group for duration of
marketing
 Categorization of Products for Lot
Release Group 3
• post licensure-approval based on protocol review
and periodic lot testing
• manufacturer must submit protocols of each lot;
samples must be submitted only when specifically
requested by the Bureau.
• written approval for the sale of each lot in Canada in
the form of a release letter
 Categorization of Products for Lot
Release Group 4
• annual notification ; (June 30 of each year) of
the lots sold in Canada
• low risk , well characterizable products
• no release letter issued
• trend analysis of the critical test
specifications.
 UNAPPROVED BIOLOGIC DRUG
Targeted Testing Regime Evaluation Group 1A Clinical Trial Material(s)
Risk Assessment of Test Group 1B Consistency Samples
Risk of obtaining incorrect result

Safety risk of incorrect result

Approved
Well Characterized
Traditional Biologic Product for Product
Lot by Lot Release Therapeutic DNA plasmid products
Therapeutic synthetic peptide
products of 40 or fewer amino acids
Monoclonal antibodies for in vivo use

UNSATISFACTORY Therapeutic recombinant DNA-derived

products
Evaluation Group 2 Additional products assessed on a

case by case basis

Targeted Testing and
Protocol Review of All Lots
With Rationale

Evaluation Group 2
Targeted Testing and
Product History Protocol Review of All Lots
Evaluation Group 3 Manufacturer History
Protocol Review of All Lots and Inspection History Or
Periodic Testing
Evaluation Group 3
Protocol Review of All Lots
and Periodic Testing

Evaluation Group 4 Evaluation Group 4

Notification and Periodic Testing SATISFACTORY Notification and Periodic Testing
Categorization of Products for Lot Release

Category Licensure Protocol Targeted Release

Review Testing Letter

1 Pre- Yes Yes Yes

Vaccines Vaccines

2 Post- Yes Yes Yes

3 Post- Yes Periodic Yes

4 Post No No No
 Lot Release Program
Summary points

On-going Assessment of Biological Drugs to

Ensure Safety and Efficacy

Four assessment categories from full and

complete testing through protocol review down
to notification and tracking
 Lot Release
a system of approval given for the release onto the Canadian
market of a specific lot of biological product based upon
certification that the lot meets appropriate in process controls
and control tests on final products.

such controls to be applied to the release of batches of the

product have been decided at the time of licensing of the
biological product (but may change).

Lot release is necessary because of the complex nature of

biological drugs.

The Lot Release program has been rationalized based on a

risk assessment model.
 Lot Release
• Factors influencing the degree of
assessment:
• Product Indication
– Age/health status/size of target population
– Disease state & duration of treatment

• Nature of the product

– Source and level of control of the raw materials
– Complexity, robustness and control of the process
– Chemical/biological complexity of the DS and DP
– Reliability/complexity of the methods used to evaluate
identity, purity, and potency
 Lot Release
• Factors considered in determining the
degree of assessment:
• Production history
– Consistency of manufacturing
– Changes in the incidence of reprocessing lots
– Incidence and seriousness of lot failures
• Inspection history
– Major quality and safety issues at OSE or cGMP
inspection
• Testing history (manufacturer and BGTD)
• Post-market experience
– Adverse drug reactions (ADRs), product
recalls/withdrawals