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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