Manufacturing Process
Rutendo Kuwana
Technical Officer, WHO, Geneva
Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and
.assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda
Finished Pharmaceutical Product Manufacturing
Manufacturing and marketing authorization
Pharmaceutical development
Formulation
Sites of manufacture
Manufacturing process
Manufacturing process controls of Critical steps and intermediates
Process validation and Evaluation
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Manufacturing site(s)
Name and street address of each facility where any aspect
of manufacture occurs including production, sterilisation,
packaging and quality control
Including any alternative manufacturers
Certificate issued by the Competent DRA according to
WHO Certification scheme for each site where a major
step of manufacturing is performed
Valid GMP certificate (may not insist if inspected by WHO)
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Manufacturing Process
Flow chart with indication of each step showing where
materials enter the process. Indication of critical steps and
in-process controls
Description of manufacturing/packaging including
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Scale
Equipment by type (e.g. tumble blender) & working capacity
Process parameters for steps, (e.g. time, temperature, pH)
Environmental conditions, e.g. relative humidity for hygroscopic
FPPs., area class for sterile FPPs
Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Manufacturing process (cont.)
Proposal for reprocessing justified with data.
Copy of master formula.
Batch manufacturing record real batch.
Sterile products sterilisation steps and/or aseptic procedures.
Description of in-process tests including plan of sampling and
acceptance limits).
Data for 3 full scale batches to support achievement of
predetermined specifications.
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Manufacturing Process Controls of Critical steps
and Intermediates
Identification of critical steps with test methods and
justified acceptance criteria
Information on quality of isolated intermediates, test
methods and justified acceptance criteria to control them
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Process Validation and Evaluation
WHO validation definition
The documented act of proving that any procedure, process,
equipment, material, activity, or system actually leads to the
expected results.
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
What should be validated ?
Any aspect of operation, including significant changes to the
premises, facilities, equipment or processes, which may
affect the quality of the product, directly or indirectly,
should be qualified and validated
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Purpose of Process Validation
Process validation is intended to establish that the proposed
manufacturing process is a suitable one and yields
consistently a product of the desired quality.
i.e. that the process is suitable and under control
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Process Validation and Evaluation
Validation is mandatory for processes including all critical steps
The aim is to show that critical steps are under control and lead
continuously to the desirable quality
Examples of critical steps (list non exhaustive)
mixing,
coating,
granulation,
emulsification,
non-standard sterilisation
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Critical Steps to Validate (Example)
Manufacturing Step
API
CPPs
Particle Size
Impact on Quality
Product Dissolution
Different lots (same source) Challenge study
RAM sieving
Pre-Mixing (before wet
granulation)
MESH#
Break lumps
Type of machine
Foreign matter
contamination
Mixing Time
Blend Uniformity
Mixing Speed
Mixing Volume
Mixing Method
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Critical Steps to Validate (Example)
Manufacturing Step
Wet Granulation
CPPs
Load Size
Mixing speed
Impact on Quality
Damp massing, API
distribution, Torque
Granulation Time
Binder amount
Damp Massing, Torque
Binder Concentration
Water Added
Feed rate
Ampere Meter
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
End Point Indicator
Critical Steps to Validate (Example)
Manufacturing Step
Final Blending
CPPs
Blending time
Blending Volume
Impact on Quality
Blend Uniformity, size
distribution, flowability
Blending Speed
Lubricant/Disintegrant Sieve#
Tabletting
Glidant Sieve #
Blend Uniformity, size
distribution, flowability,
dissolution
Tabletting Speed
Assay, content uniformity,
dissolution, physical and
microbiological properties of
tablets
Dwell Time
Hopper Level
Compression Force
Feeder Speed
IPC Adjustment
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
IPC Data
Identification of some CQAs (Tablets)
Quality Attributes
(Final Blend,
Tablets)
Impact on
Patient
Product
Process
Blend Uniformity and
CU
Size Distribution
% Compressibility
LOD
Max. Hold Time
Appearance
Identification
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Process Validation and Evaluation
Details required on first 3 production batches
Batches
batch number
batch size
place and date of manufacture
batch number of API(s)
yield
batch purpose (validation, stability, clinical trial )
Process
equipment
process parameters
validation protocol.
Results
critical steps
in process control
finished product specification
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Other requirements
Concurrent validation carried out during normal production
on the first 3 consecutive production batches
OR
For well-established processes
process data, in-process controls and quality controls on a
total of 10- 25 batches to present a statistically significant
picture
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Alternatives
If validation data (on production scale batches) are not
available submit
validation protocol,
commitment that validation report will be submitted later
for evaluation,
commitment that data will be available in case of
inspection,
commitment that WHO will be informed of any significant
deviation.
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Validation Protocol
Objective, Scope and Rationale
Brief description of the process with summary of critical steps and parameters to be
followed during validation, process flow chart
specifications and analytical methods of the FPP at release,
details of analytical procedures and limits,
List of equipment to be used
sampling plan and acceptance criteria
Defined CPPs to be monitored and CQAs to be tested
proposed timeframe
Validation report when submitted should include results for each batch,
certificates of analysis, batch production records, report on unusual
findings, modifications, observations and conclusions
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Validation Report Outline Each Batch
Objective
Scope
Validation Batch Information
Deviation report
Critical Quality Attributes (CQAs) Test Data
Statistical Evaluation of CQAs
Conclusion
NB: One batch, One Report
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
Validation Report Outline Final
Objective
Scope
Validation Batch Information Summary
Summary on CQAs and Test Data evaluated
Overall Conclusion
Recommendation
NB:Three Batches, One Report
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Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda