Manufacturing Process and Validation

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
2| 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)

Development of manufacturing process
Pre- formulation
Formulation
Pilot manufacture
Industrial Scale
4
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
5
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
6
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.
7
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
8
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)
9
Manufacturing Process Controls of Critical steps and
Intermediates
Manufacturing step Test Item Methods Acceptance criteria
After Step 1.1 Yield By weighing 99-110%
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
10 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Manufacturing Process Controls of Critical steps and
Intermediates
Test Item 100/270mg Tablets

Average Mass – Layer 1 421- 447mg
Average Mass - layer 1+2 679 - 721mg
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

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

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
13
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”

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

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

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

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 (low-
dose 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
18
 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
19
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)
20
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
21
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
22
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
23
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
24
Other requirements
For well-established processes/product

for the manufacturer – report on review of NLT 10 batches
manufactured in the past 12 months

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.

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.

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.

Use of analytical methods - generics
Clinical Pharmaceutical Methods
At initial phase of pharmaceutical development
To determine To develop a stable and reproducible To understand the profile of -
bioavailability in formulation for the manufacture related substances and to study
healthy volunteers of bioequivalence, dissolution, stability and start measuring the
stability and pilot-scale validation impact of key product and
batches manufacturing process parameters
on consistent FPP quality
At advanced phase of pharmaceutical development

To prove bioequivalence To optimize, scale-up, and transfer a To be robust, transferable, accurate,
after critical stable and controlled and precise for specification
variations to the manufacturing process for the setting, stability assessment, and
prequalified dossier prequalification product QC release of prequalified
batches

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Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

 Manufacturing and marketing authorization

2| Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

 Certificate issued by the Competent DRA according to

 Valid GMP certificate (may not insist if inspected by WHO)

3| Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Relationship between method of manufacture and process

Process should address the need and value of in process

Process evaluation and validation should justify reduction

 Used to generate information from laboratory through

 Evidence that scale up will not result in loss in quality

 Should show that variations in batch size will not

 Description of manufacturing/packaging, including

 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

 Intermediates isolated during process e.g tablet cores in

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%

10 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Test Item 100/270mg Tablets

11 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

WHO validation definition

The documented act of proving that any procedure, process, equipment,

Process validation is the collection and evaluation of data, from process

12 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Differentiate between the following generics:

New FPPs (new for manufacturer, not marketed yet)

“Any aspect of operation, including significant changes to the

14 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Process validation is intended to establish that the proposed

i.e. that the process is suitable and under control

15 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Examples of critical steps (list non exhaustive)

16 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

17 | Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Extensive sampling and testing during process, for example (tablets)

 Parenteral products, aseptically filled (if terminal sterilization is not

 Challenge experiments to determine

Laboratory scale batches (small size),

 Compliance with FPP specifications alone inadequate to

 Manufacturer may not have completed formal validation

 Important to link development and evaluation of

 To be used for applications where production scale

 To outline the formal validation process to be conducted

 Data should be available for verification post -

- short description of the process including critical processing steps or

- FPP release specifications

- Details of analytical methods

- IPC proposed and acceptance criteria

- additional testing and analytical validation