1-3_manufacturingprocess_processvalidation

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MANUFACTURING PROCESS AND VALIDATION

Rutendo Kuwana

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


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Assessment of Interchangeable Multisource Medicines, Kenya, August 20092|

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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Manufacturing site(s)

Name and street address of each facility where any aspectof 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 20094|4

Development of manufacturing process

Pre- formulation

Formulation

Pilot manufacture

Industrial Scale


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Relationship between method of manufacture and processvalidation 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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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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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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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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Manufacturing processControls 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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Manufacturing Process Controls of Critical steps and

Intermediates

Acceptance criteriaMethodsTest ItemManufacturing step

99-110%By weighingYieldAfter Step 1.1


98-100%By weighingYieldAfter Step 2.1.3

98-100%By weighingYieldAfter Step 2.2.3

See table belowVisual inspectionAppearanceAfter Step 3.2

See table below-ThicknessAfter Step 3.2

See table belowIn-houseAverage massAfter Step 3.2

See table belowEur. Ph.HardnessAfter Step 3.2

1%Eur. PhFriabilityAfter Step 3.2

15minEur. PhDisintegration timeAfter Step 3.2



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Manufacturing Process Controls of Critical steps and

Intermediates

100/270mg TabletsTest Item421- 447mgAverage Mass Layer 1

679 - 721mgAverage Mass - layer 1+2

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

Appearance

4.1-4.4mmThickness

>100NHardness


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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 processdesign stage throughout production, which establishes scientific

evidence that a process is capable of consistently delivering qualityproducts

US FDA


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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 to3 years

result/trend/statistical analysis & discussion

Rejected batches excluded - submit failure investigation


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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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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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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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Details required on first 3 production batches

Batches

batch numberbatch 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 stepsin process control

finished product specification


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Validation new product

Concurrent / prospective validation (2)

Parenteral products, aseptically filled (if terminal sterilization is notpossible)

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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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 or100,000 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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Process Validation Data

Compliance with FPP specifications alone inadequate todemonstrate 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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Process Validation Scheme/Protocol

To be used for applications where production scalebatches 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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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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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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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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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 fromnew sources.

A tabulation of Batch Analysis data (including in-process test results and finished productquality control results) together with statistical and trend analysis where appropriate.

A review of all out-of-specification and related investigations, with indication of batchesthat failed to meet specification(s)

A review of all deviations.

All changes carried out

Quality-related returns, complaints and recalls.


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Alternatives

If validation data (on production scale batches) are notavailable submit

validation protocol,

commitment that validation report will be submitted laterfor evaluation,

commitment that data will be available in case ofinspection,

commitment that WHO will be informed of any significantdeviation.


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Analytical Methods

Process knowledge depends on accurate and precisemeasuring 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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