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 After Step 1.1 After Step 1.2 After Step 2.1.3 After Step 2.2.3 After Step 3.2 After Step 3.2 After Step 3.2 After Step 3.2 Test Item Yield Yield Yield Yield Appearance Thickness Average mass Hardness Methods By weighing By weighing By weighing By weighing Visual inspection In-house Eur. Ph. Acceptance criteria 99-110% 100-110% 98-100% 98-100% See table below See table below See table below See table below

After Step 3.2

After Step 3.2 After Step 3.2

Friability
Disintegration time Yield

Eur. Ph
Eur. Ph By weighing

1%
15min 97-100%

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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Manufacturing Process Controls of Critical steps and Intermediates

Test Item
Average Mass Layer 1
Average Mass - layer 1+2 Appearance

100/270mg Tablets
421- 447mg
679 - 721mg 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 Hardness

4.1-4.4mm >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.

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

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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
To determine bioavailability in healthy volunteers

Pharmaceutical
To develop a stable and reproducible formulation for the manufacture of bioequivalence, dissolution, stability and pilot-scale validation batches

Methods
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 initial phase of pharmaceutical development

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

To be robust, transferable, accurate, and precise for specification setting, stability assessment, and QC release of prequalified batches

Assessment of Interchangeable Multisource Medicines, Kenya, August 2009