MANUFACTURING PROCESS AND VALIDATION
Rutendo Kuwana
Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Manufacturing site(s)
Name and street address of each facility where any aspect
of manufacture occurs including production, sterilisation,
packaging and quality control
Blocks and Units should be clearly stated
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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Development of manufacturing process
Pre- formulation
Formulation
Pilot manufacture
Industrial Scale
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Development of manufacturing process
Relationship between method of manufacture and process
validation data
Process should address the need and value of in process
controls
Process evaluation and validation should justify reduction of
some tests from routine
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Development of manufacturing process
Scale Up Data
Used to generate information from laboratory through
pilot to production scale batch
Evidence that scale up will not result in loss in quality
Should show that variations in batch size will not
adversely alter FPP characteristics
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Manufacturing process
Information required
Flow diagram
critical steps in-process controls
Description of manufacturing/packaging, including
Scale
Equipment by type (e.g. tumble blender) & working
capacity
Process parameters for steps, e.g. time, temp, pH
Environmental conditions, e.g. rel. humidity for
hygroscopic FPPs.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Manufacturing process (2)
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
Data for 3 full scale batches to show achievement of
predetermined specifications
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Manufacturing process
Controls of critical steps and intermediates
Critical steps
Acceptance criteria (justified)
Test methods (cross reference acceptable)
Intermediates isolated during process e.g tablet cores in
film-coated tablet production
Acceptance criteria (justified if not Compendial)
Test methods (cross reference acceptable)
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Manufacturing Process Controls of Critical steps and
Intermediates
Manufacturing step
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Test Item
Methods
Acceptance criteria
After Step 1.1
Yield
By weighing
99-110%
After Step 1.2
Yield
By weighing
100-110%
After Step 2.1.3
Yield
By weighing
98-100%
After Step 2.2.3
Yield
By weighing
98-100%
After Step 3.2
Appearance
Visual inspection
See table below
After Step 3.2
Thickness
See table below
After Step 3.2
Average mass
In-house
See table below
After Step 3.2
Hardness
.Eur. Ph
See table below
After Step 3.2
Friability
Eur. Ph
1%
After Step 3.2
Disintegration time
Eur. Ph
15min
After Step 3.2
Yield
By weighing
97-100%
Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Manufacturing Process Controls of Critical steps and
Intermediates
Test Item
100/270mg Tablets
Average Mass Layer 1
447mg- 421
Average Mass - layer 1+2
721mg - 679
Appearance
Round, biconvex, bilayered tablet;
one layer is yellow coloured and may
be mottled, and the other one is white
to slightly yellow, with a break line,
engraved "GP" on one side, and
"100" on the other side
Thickness
4.1-4.4mm
Hardness
100N<
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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.
Process validation is the collection and evaluation of data, from process
design stage throughout production, which establishes scientific
evidence that a process is capable of consistently delivering quality
products
US FDA
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Process validation & evaluation
Differentiate between the following generics:
New FPPs (new for manufacturer, not marketed yet)
FPPs that have been newly developed by the manufacturer, though it will be
a generic
Full validation required
Established FPPs
The manufacturer has manufactured & marketed this FPP for quite some
time
Submit review of report for 10 recent consecutive batches
Manufactured within the preceding year. If less than 10 batches, may extend the period to
3 years
result/trend/statistical analysis & discussion
Rejected batches excluded - submit failure investigation
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Validation new product
Concurrent / prospective validation (1)
Concurrent validation
Carried out during normal production
First 3 production batches (prospective validation)
In-process controls are set on outcome of validation
Extensive sampling and testing during process, for example (tablets)
planned sampling on mixing / granulation stages for content uniformity (lowdose FPPs & FDCs !)
A large number of tablets for mass and/or content uniformity, hardness,
friability and even dissolution
Sampled according to plan during process
Statistical analysis of results with conclusions
To be within acceptance criteria
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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Validation new product
Concurrent / prospective validation (2)
Parenteral products, aseptically filled (if terminal sterilization is not
possible)
Filling ampoules with culture media, then
Incubation and control of microbial growth
Level of contamination: 0.1%
Challenge experiments to determine
robustness of process
effect of material variations, such as particle size can be carried out on
experimental batches e.g. stability of granulate over time
Effect in case of unplanned stoppage
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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Validation new product
Concurrent / prospective validation (4)
Laboratory scale batches (small size),
To support e.g. formulation and packaging development
Pilot batches
Used e.g. in stability and safety/efficacy studies
Size for oral solid dosage forms: the largest of 10% of production scale or
100,000 units
Productions scale
For full validation and stability studies
Scale-up / scale down after registration
Up to10-fold compared to the original batch size (minor amendment/change)
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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Process Validation Data
Compliance with FPP specifications alone inadequate to
demonstrate validation of processes and control over
process
Manufacturer may not have completed formal validation
on production scale batches
Important to link development and evaluation of
laboratory and pilot scale batches, process development
and optimisation
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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Development of manufacturing process
Process Validation Scheme/Protocol
To be used for applications where production scale
batches not yet produced
To outline the formal validation process to be conducted
on production scale batches (at least 3 consecutive
batches)
Data should be available for verification post registration
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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Development of manufacturing process
Process Validation Scheme/Protocol (2)
Information required
- short description of the process including critical processing steps or parameters to be monitored
- FPP release specifications
- Details of analytical methods
- IPC proposed and acceptance criteria
- additional testing and analytical validation
- sampling plan where, when and how samples are taken
- details of methods for recording and evaluating of results
- proposed timeframe
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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Development of manufacturing process
Process Validation Report
After validation
Batch analytical data
Certificates of analysis
Batch manufacturing records
Report on unusual findings, modifications or changes found necessary
with appropriate rationale
Conclusions
Significant deviations to be informed to DRA and regulatory approval
required before implementation
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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Other requirements
For well-established processes/product
for the manufacturer report on review of NLT 10 batches
manufactured in the past 12 months
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Review report for established FPP should contain at
least the following
List of reviewed batches - batch numbers, manufacturing dates and batch size. Any
differences from the prequalified/approved batch size should be clarified.
Review of starting materials (active pharmaceutical ingredients (APIs) and excipients)
list of sources (API), compliance with specifications
Review of primary packing materials used in the FPP, including reference to those from
new sources.
A tabulation of Batch Analysis data (including in-process test results and finished product
quality control results) together with statistical and trend analysis where appropriate.
A review of all out-of-specification and related investigations, with indication of batches
that failed to meet specification(s)
A review of all deviations.
All changes carried out
Quality-related returns, complaints and recalls.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Analytical Methods
Process knowledge depends on accurate and precise
measuring techniques on starting material, intermediates
and finished product.
For data to be of value the analytical tests must be
scientifically sound
Validated analytical methods are not required during product
and process development activities. The methods should
however be scientifically sound (e.g. specific, sensitive,
accurate), suitable and reliable for the specified purpose.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Use of analytical methods - generics
Clinical
Pharmaceutical
Methods
At initial phase of pharmaceutical development
To determine
bioavailability in
healthy volunteers
To develop a stable and
reproducible formulation for the
manufacture of bioequivalence,
dissolution, stability and pilotscale validation batches
To understand the profile of related substances and to study
stability and start measuring the
impact of key product and
manufacturing process
parameters on consistent FPP
quality
At advanced phase of pharmaceutical development
To prove
bioequivalence
after critical
variations to the
prequalified dossier
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To optimize, scale-up, and transfer a
stable and controlled
manufacturing process for the
prequalification product
Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
To be robust, transferable, accurate,
and precise for specification
setting, stability assessment,
and QC release of prequalified
batches
