MANUFACTURING OF API
AND INTERMEDIATES
Overview
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Introduction
Scope
Responsibilities
The Requirements
 General Considerations
 Prevention of Cross-Contamination
 Batch Manufacturing Records
 And the others (13 items)
Introduction
• Manufacture of active pharmaceutical ingredients
(APIs) and intermediates as finished product, must
follow well-defined operating principles
System and Principles must be well-defined
• Manufacture must comply with current Good
Manufacturing Practices (GMPs) and with the
corresponding registration dossiers
GMP Compliance & Regulatory Compliance
2. Scope
This presentation applies to all
manufacturing sites and subcontractors,
who manufacture active pharmaceutical
ingredients and intermediates
Based on ICH Q7 (EU GMP part II)
3. Responsibilities
• Site Management is responsible for ensuring that
adequate resources are in place to comply with the
regulatory requirements
Adequate Resources to be provided
• Site Quality Management is responsible for ensuring that
there are systems and procedures in place for the
manufacturing of APIs and Intermediates
Systems and Procedures must be in place.
4. Requirements (1)
 General Considerations
 Prevention of Cross-Contamination
 Computerised Systems
 Documentation
 Batch Manufacturing Records
 Review of Batch Manufacturing Records
 Manufacturing Process
 In-process Sampling and Testing
 Change Control
4. Requirements (2)
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Analytical, Biological and Microbiological
Tests
Water
Recycling of Recovered Materials and
Solvents
Reprocessing
Reworking
Wastewater and Materials
Storage
4. 1. General Considerations (1)
• Manufacturing operations must be performed
and supervised by trained and qualified
personnel
• Personnel must wear garments and protective
clothing suited to the operation performed and
taking into Account any specific Health, Safety
and Environment (HSE) requirements.
4. 1. General Considerations (2)
• Product handling operations such as receipt,
quarantining, sampling, storage, labelling,
packaging and transfer must be conducted in
a way to prevent any risk of crosscontamination and must be described in
appropriate procedures
Specific requirements for Highly Active
Substances. Dedicated and self-contained
facilities must be used for these materials,
e.g. beta-lactams, hormones, cytotoxics.
4. 1. General Considerations (3)
• All equipment, products, and containers must be
clearly labelled and identified. Labels must be
designed to be securely affixed, legible, and
must not fade or deteriorate with time
• Connections between piping (lines, flexible
tubing, etc) and other manufacturing equipment
used to transfer products must be controlled.
4. 1. General Considerations (4)
• Only authorised personnel must be allowed to enter in the
manufacturing areas. Site personnel must accompany visitors within
manufacturing areas
• All company personnel and visitors to the site must be under
controlled access and exit at all times
• Visitors access and exit must be authorised and documented
• Visitors must be accompanied by site personnel at all times unless
training in GMPs specific to the area is provided and documented.
4. 1. General Considerations (5)
• Equipment used to manufacture intermediates and APIs
must be qualified and uniquely identified and be part of
a preventive maintenance program
• Equipment, instrumentation, computerised and/or
control systems, facilities and utilities used in
conjunction with the above must be qualified, and
systems (e.g. water systems and computerised systems)
and processes must be validated and maintained in a
documented state of control
4. 1. General Considerations (6)
• Critical measuring equipment must be in calibration and be
part of a calibration program
• All equipment and instruments that could have an impact on
product quality, safety or efficacy must be tracked and
maintained under a calibration and maintenance program
• All calibrations and maintenance must be documented and the
records of those activities must be archived
• Calibration is essential to maintain product quality, personnel
and environmental safety during operation. It is an important
step for qualification.
4. 1. General Considerations (7)
• Starting materials, raw materials and packaging materials
used to manufacture intermediates and APIs must meet
predetermined specifications as defined in the registration
dossiers and be released by the Quality Unit according to site
procedures
• All specifications developed for APIs and intermediates must
contain at a minimum the following attributes: Appearance
and/or Description, Identity, Assay, Impurities
• Quality Unit must establish a system to release or reject raw
materials, intermediates, packaging and labelling materials
(ICH Q7A, under 2.2)
4. 2. Prevention of CrossContamination (1)
• Measures must be taken during manufacture to
prevent/minimise any contamination risk specifically when
manufacturing areas are not dedicated to a single product
• Air filtration equipment and environmental zones of the finishing
rooms must be subject to the requirements of the Directive
“Environmental Zoning & Air Handling Systems”
• Prevention of contamination. Cleaning of non-dedicated
equipment used for the final steps must be validated
• Environmental Zoning & Air Handling System requirements for
the final steps: drying, milling, filling.
4. 2. Prevention of CrossContamination (2)
• Different batches of product or product in different
phases must not be loaded or unloaded
simultaneously in the same area/room
• Rooms in which packaging and labelling operations
are performed must be inspected immediately before
use in order to ensure that all non-relevant packaging
components have been removed. This operation must
be reported in the batch record. (ICH Q7A, 9.44)
• If operations on different products are carried out
simultaneously or consecutively in the same room, the
operations must be segregated and controlled.
4. 3. Computerised Systems
• Any computerised system which may have an impact of
product quality or which deals with any GMP related data
must be validated
• Good Practices for Computerised Systems
• Computerised Systems Validation
• The scope and extend of the validation activities must be
commensurate with the GxP risk and complexity of the
system
• Validation must be based on a documented User
Requirement Specification.
4. 4. Documentation
• All documents related to the manufacture
of intermediates and APIs (e.g. process
description, batch manufacturing records),
must be prepared, checked, approved and
issued following written procedures.
ICH Q7, Chapter 6: Documentation and Records
4. 5. Batch Manufacturing Records
(1)
• For each batch of intermediate or API, batch
manufacturing record(s) with its associated batch
number must be compiled, checked for
appropriateness with the Master Batch
Manufacturing record, and signed before use
• Batch Manufacturing Records must include but not
limited to:
 Dates and when appropriate, times
 Reference to each major equipment used (e.g. reactor,
drier, mills, etc.)
 Description of packaging and labelling materials used
4. 5. Batch Manufacturing Records
(2)
• Batch number of the manufactured product, raw materials,
starting materials, intermediates, any reprocessed, or reworked material, and packaging materials
• Any physical and chemical parameters
• Critical process data
• Analytical data on the finished product, if available
• Sampling operations
• Signature or initials of each operator who has performed a
critical step and of each operator who has checked it
• In-process control test results
4. 5. Batch Manufacturing Records
(3)
 Representative(s) label(s) used to identify the finished product batch
 Yields obtained at defined stages
 Any deviation reported during manufacture with all relevant
comments
Individual manufacturing steps must be signed
(or initialled) and dated.
• A similar list is provided in ICH Q7, under 6.52
• A list for Master Batch Records: under 6.41
4. 6. Review of Batch
Manufacturing Records
• Batch manufacturing records must be reviewed
and approved by Manufacturing and Quality
departments according to site procedures
• Any deviation, investigation, comment and any
report of an Out-of-Specification (OOS) result
must be an integral part of the batch record and
must be reviewed before a decision is taken on
the release/reject of the batch.
• ICH Q7, Chapter 6.7
4. 7. Manufacturing Process (1)
• Critical steps and methods must be defined for each
manufacturing process through a scientific rationale
• Critical manufacturing steps and critical cleaning methods
must be validated according to site procedures
• What is the definition of “critical”?
“Critical” in this context describes a process step, process
condition, test requirement or other relevant parameter or
item that must be controlled within pre-determined criteria to
ensure that the API meets its specification. (ICH Q7)
4. 7. Manufacturing Process (2)
• Critical process parameters must be identified,
monitored and/or recorded/reported. They must be
checked and signed (initialled) by a second person
• Any deviation to critical processing and process
parameters or any discrepancy in the yield range for
critical steps must be documented and investigated in
order to assess its potential impact on product quality.
• Control all steps and parameters!
• Validate the critical ones!
4. 8. In-process Sampling and
Testing
• Sampling during manufacture and in-process control tests with
defined limits when applicable, must be described in
documents/procedures
• Blending batches of finished products intermediate or API is allowed
providing this is a condition of the registration dossiers and complies
with specifications. Under this condition expiry or retest date should
be based on the date of the oldest batch
 Blending Batches in ICH Q7, Chapter 8.4
 “Out-of-Specification batches should not be blended with other batches
for the purpose of meeting specifications.”
4. 9. Change Control
• Any change associated with the manufacture of
active pharmaceutical ingredients or
intermediates must be in compliance with the
site change control procedure
ICH Q7, Chapter 13
4. 10. Analytical, Biological &
Microbiological Testing
• Laboratory tests must be conducted on
each batch of active pharmaceutical
ingredient and where applicable on each
batch of intermediate as described in the
registration dossiers in order to confirm
compliance with the approved
specifications
ICH Q7, Chapter 11 (Laboratory Controls)
4. 11. Water
• *Water used in the manufacturing process
must be suitable for its intended use and
meet pre-defined specifications
ICH Q7, Chapter 4.3 (Water)
*We have a separate guidance document which goes into detail on Water: Type, Production, Distribution,
Use & Storage and Operations and Control of Water Systems.
4. 12. Recovery of Materials &
Solvents
• Recovered materials and solvents must be recycled
and tested to pre-defined specifications according to
site procedures and in compliance with registration
dossiers
• Where appropriate, the number of re-cycles allowed
must be defined and the recovery process should be
validated.
ICH Q7, Chapter 14 (Rejection and Re-use of
Materials)
4. 13. Reprocessing; 4.14
Reworking
• For further information refer to the
guidance document entitled
“Reprocessing, Reworking and Reincorporation”.
• ICH Q7, Chapter 14 (Rejection and Re-use
of Materials)
4. 15. Wastewater and
Materials
• Wastewater and materials (solids, fluids or
secondary products derived from manufacture)
must be discarded in a way that satisfies Health,
Safety and Environmental (HSE) requirements.
• ICH Q7, Chapter 4.6 (Sewage and Refuse):
“Sewage, refuse, and other waste… should be
disposed of in a safe, timely, and sanitary
manner. Containers and/or pipes for waste
material should be clearly identified”
4. 16. Storage
• Finished products must be handled and stored in
controlled/monitored areas under conditions to
prevent degradation and/or contamination.
• Refer to our guidance document on Warehousing and
Good Distribution Practices
• ICH Q7, Chapter 7.4 (Storage)
• Guide to Good Storage Practices for Pharmaceuticals
Annex 9, WHO Technical Report Series 908, 2003
Summary
• It is important that you have all operations
involved in the preparation of an API under
appropriate control, by:
 Having defined the critical process steps
 Having established a robust process (PAT, QbD)
 Having performed a process validation with
continuing verification
 Using an effective Change Control System
 Investigating discrepancies, deviations; and
 Learning from problems, errors and mistakes.
Thank You
Any Questions