manufacturing process and validation rutendo kuwana training workshop: assessment of interchangeable...

MANUFACTURING PROCESS AND VALIDATION

Rutendo Kuwana

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

Assessment of Interchangeable Multisource Medicines, Kenya, August 20092 |

Finished Pharmaceutical Product ManufacturingFinished 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


Manufacturing site(s)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)

Assessment of Interchangeable Multisource Medicines, Kenya, August 20094 |4

Development of manufacturing processDevelopment of manufacturing process

Pre- formulation

Formulation

Pilot manufacture

Industrial Scale



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



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


Manufacturing processInformation required

Manufacturing processInformation 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.


Manufacturing process (2)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


Manufacturing process Controls of critical steps and intermediates

Manufacturing process Controls of critical steps and intermediates

Critical stepsAcceptance 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)


Manufacturing Process Controls of Critical steps and Intermediates


Manufacturing stepTest ItemMethodsAcceptance criteria

After Step 1.1YieldBy weighing99-110%


After Step 2.1.3YieldBy weighing98-100%

After Step 2.2.3YieldBy weighing98-100%

After Step 3.2AppearanceVisual inspectionSee table below

After Step 3.2Thickness-See table below

After Step 3.2Average massIn-houseSee table below

After Step 3.2HardnessEur. Ph.See table below

After Step 3.2FriabilityEur. Ph≤1%

After Step 3.2Disintegration timeEur. Ph≤15min





Test Item100/270mg TabletsAverage Mass – Layer 1421 -447mg

Average Mass - layer 1+2 679 - 721mg

AppearanceRound, 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

Thickness4.1-4.4mm

Hardness>100N


Process Validation and EvaluationProcess 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 & evaluationProcess 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


What should be validated ?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 ValidationPurpose 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


Process Validation and EvaluationProcess 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


Process Validation and Evaluation Details required on first 3 production batches

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 …)

Processequipmentprocess parametersvalidation protocol.

Resultscritical stepsin process controlfinished product specification


Validation “new” productConcurrent / 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




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




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)


Process Validation DataProcess 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


Development of manufacturing processProcess Validation Scheme/Protocol

Development of manufacturing processProcess 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


Development of manufacturing processProcess Validation Scheme/Protocol (2)Development of manufacturing processProcess 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


Development of manufacturing processProcess Validation Report

Development of manufacturing processProcess 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


Other requirementsOther requirements

For well-established processes/productfor 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

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.


AlternativesAlternatives

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 MethodsAnalytical 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 - genericsUse 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 pilot-scale 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 developmentTo prove bioequivalence after critical variations to the prequalified dossier

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

manufacturing process and validation rutendo kuwana training workshop: assessment of interchangeable...

Documents

manufacturing sites

process tests data

capacity process parameters

evaluation slide

routine slide

major step of manufacturing

scale equipment

scale batches