2005.03.03. Dr. Pogány - WHO, Shanghai 1/58 Workshop on Quality Assurance and GMP of Multisource...

2005.03.03. Dr. Pogány - WHO, Shanghai 1/58

Workshop on Quality Assurance and GMP of Multisource HIV/AIDS medicines

János Pogány, pharmacist, PhD, consultant to WHO

Shanghai, 01 March 2005E-mail: [email protected]

QUALIFICATION and VALIDATION I.


Subjects for Discussion

1. Regulatory background, definitions

2. Characteristics of processes

3. Validation master plan (VMP)

4. Pharmaceutical manufacturing process validation (tablet-making)

5. Concluding remarks


WHO GMP and Guidelines Guideline on Submission of Documentation for

Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis.

WHO good manufacturing practices (GMP): main principles for pharmaceutical products – Section 4. Validation of manufacturing processes.

Supplementary guidelines on good manufacturing practices (GMP): Validation (2003) – Draft.


Qualification QUALIFICATION is the „Action of proving that any

premises, (pharmaceutical utility) systems and items of equipment work correctly and actually lead to the expected results. The meaning of the word “validation” is sometimes extended to incorporate the concept of „qualification”.

REQUALIFICATION is the main part of the preventive maintenance programme of proving that any premises, (pharmaceutical utility) systems and items of equipment work correctly and keep on leading to the expected results. (normal wear and tear)


Validation VALIDATION is the „Action of proving, in

accordance with the principles of GMP, that any procedure, process, equipment, material, activity or (pharmaceutical utility) system actually leads to the expected results (see also qualification)”.

REVALIDATION is a part of the change control system of proving that any procedure, process, equipment, material, activity or (pharmaceutical utility) system actually keeps on leading to the expected results.


Qualification - Validation

Regulatoryrequirements

DQ,IQ,OQ inputs

DQ,IQ,OQ process

DQ,IQ,OQ outputs Process

Qualification Verification

Validation

Premises, equipment and supporting utilities must be qualified to operate in a validated process.


Technical pharmacy Pharmaceutical production system

(from purchasing API to packaging FP) Utility support system (HVAC, water, HPLC, etc.

equipment containing many items) Process (tablet making) (Unit) operation (granulation, compression) Step (sifting, sizing) Procedure, method, technique (SOP)


4.10 Scientific approach „Processes and procedures should be established on the basis

of the results of the validation performed.”

Objectives To prove that the tests, measurements, results and

interpretation of formal studies on (manufacturing) processes and procedures/methods are appropriate and accurate.

To stabilize new processes (to reduce variability, to increase batch to batch consistency of quality attributes of products).

To reduce defect levels (standardize yields). To reduce production costs.


Measure of variation (spread of data)

95.46%68.26%


Mean (average) chart

Normal variation

due to common causes

UCL Upper control limit

LCL Lower control limit

Abnormal variation of process – special causes

Abnormal variation of process – special causes

average = mean


Causes of variation Man (different operators - lack of proper training)

Machine / equipment (variation of tablet weight)

Measurement (lack of calibration)

Method (accuracy of validated analytical methods)

Material (batch-to-batch variation of the same crystal

form – different crystal forms (ASA)]

Environment (OoS T and RH in capsule filling)


Process under control Most points fall near the central line (68% within

one σ) A few points fall near the control limits (5% in

the third σ) Points shold balance on both sides of the mean Points should cross the mean line often. Points should show a random pattern (no trends,

cycles, clustering)


UNDER CONTROL

OUT OF CONTROL


Innovator FPPs

Well-established, multisource, generic FPPs


GMP, QUALIFICATION and

VALIDATION STARTS WITH

DESIGN + CONSTRUCTION

OF FACILITIES AND

PURCHASING EQUIPMENT


Qualification Stage Validation Stage

Key elements Design Installation Operation Prospective Concurrent

Premises and Engineering phase Manufacturing Start-Up

Equipment

VMP Validation Protocols Validation Reports

Product and Process Developmental Phase Scale-Up Phase Manufacturing Phase

Validation of Critical variables Process Process & cleaning

analytical and Process optimization validation

methods selection Revalidation

Quality Development

VALIDATION MASTER PLAN (VMP)

ILLUSTRATIVE ISSUES


4.1-4.2 Validation master plan

1. „In accordance with GMP, each pharmaceutical company should identify what qualification and validation work is required to prove that the critical aspects of their particular operation are controlled.

2. The key elements of a qualification and validation programme of a company should be clearly defined and documented in a validation master plan (VMP).”


Project oriented VMP Construction of new premises

Major renovation or additions to existing premises

First time validation of previously unvalidated processes (ARV FPPs)

Automation or computerized implementations that span a number of applications


Validation master plan The VMP is a summary document and should

therefore be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such as Policy Documents (Quality Manual), SOP's and Validation Protocols/Reports.


Content of VMP Approval (top management and all participating

departmental heads) Scope [separate VMPs for manufacturing processes,

pharmaceutical utility systems (e.g. HVAC, water)]. Responsibilities Production and QC premises (including controlled

environments)

Process and QC equipment

Pharmaceutical air (HVAC) and water systems


Content of VMP All critical utilities (such as compressed air, steam and

cooling liquids)

Computer control systems

Manufacturing processes

Product specifications including prospective IPC acceptance criteria

QC and IPC methods


Content of VMP Equipment cleaning

Validation requirements

Worker and environment safety

Change Control/Revalidation

Training requirements

Documentation requirements

Security plans

DESIGN,INSTALLATION and

OPERATION

QUALIFICATION


4.3 Documentary evidence

(a) the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements for GMP (design qualification or DQ);

(b) the premises, supporting utilities and equipment have been built and installed in compliance with their design specifications (installation qualification or IQ);


DQ and IQ DQ protocols and reports

GMP VMP National law Engineering design and construction documents

Do not start IQ before DQ has been completed! IQ/OQ protocols and reports

Above inputs + machine manuals Separate VMPs for HVAC and water systems

Do not start OQ before IQ has been completed!


4.3 Documentary evidence

(c) the premises, supporting utilities and equipment operate in accordance with their design specifications (operational qualification or OQ);

(d) a specific process will consistently produce a product meeting its predetermined specifications and quality attributes (process validation or PV, also called performance qualification or PQ).


Workshop on Quality Assurance and GMP of Multisource HIV/AIDS medicines

Tablets

MANUFACTURING PROCESS VALIDATION


Risks in manufacturing processes Small quantity of waste creates serious danger to

health (1/3 of 5% dextrose infusion was not sterile, Evans Medical, 1972)

Low chance that patient or doctor recognizes non-conformance to specification in time (DEG in glycerol, 1996 - Haiti)

Limitations of sampling Percent of nonconformance:

0,1 1,0 5,0 10,0 Percent probability of release:

98 82 36 12


SAMPLING PROBLEM

The whole batch is released to the patient

But only the sample is tested

BATCH

Sample


Types of process validation

EXPERIMENTAL APPROACHPROSPECTIVE VALIDATION (R&D)

CONCURRENT VALIDATION (FIRST ≥3 BATCHES)

ANALYSIS OF HISTORICAL DATARETROSPECTIVE VALIDATION

(DIFFERS CONCEPTUALLY FROM THE EXPERIMENTAL APPROACH)


4.4 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.”


4.8-4.9 Protocols and reports Validation studies are an essential part of GMP

and should be conducted in accordance with predefined and approved protocols.

A written report summarizing the results recorded and the conclusions reached should be prepared and stored.


Essential parts of the process validation protocol

Short description of the process with a summary of the critical processing steps or critical parameters to be monitored during validation.

Additional testing intended to be carried out (e.g. with proposed acceptance criteria and analytical validation as appropriate).

Sampling plan — where, when, how and how many samples are taken.

Details of methods for recording and evaluation of results.


Illustrative variables of wet granulationProcess step Control or manipulate

(independent) variablesMeasured responses or output (dependent) variables

CrystallizationMicronization

Particle sizeBulk density

Dissolution timeGranulation and granule variables

Pre-mixing Speed, time, order of addition

Blend uniformity

Wet kneading Batch (load) sizeSpeed Impeller Chopper Spraying rateVolume of binder solutionGranulation time

End-point amperage Impeller Chopper Additional solvent volume


Illustrative variables of wet granulationProcess step Control or manipulate


Drying Inlet air temperature (seasonal variation)Drying time (seasonal variation)Cooling time (if applicable)

Outlet air temperatureLODMoisture content

Sizing Screen type and size

Feed rate

Granule size distribution (variation of sub-batches)

Blending Batch size (sub-batches)SpeedBlending time

Blend uniformityBulk density untapped tappedFlowabilityYield


Illustrative variables of compression and film-coating

Process step Control or manipulate (independent) variables

Measured responses or output (dependent) variables

Compression

Machine speedGranule feed ratePrecompression forceCompression forcePunches and dies

Weight variationContent uniformityFriabilityHardnessThicknessDisintegrationDissolution time and profileYield

Film-coating Inlet air temperature (season)

Inlet air flow

Spray rate

Spray atomizing pressure

Outlet air temperature

Tablet-bed temperature

Coat quality

Yield


Illustrative variables of tablet packagingProcess step Control or manipulate


Blistering Machine speedMachinability of blister materialForming temperatureForming pressureSealing temperatureSealing pressure

Leak testingAppearanceMinimum information is legibleYield

Bulk packing

Tablet counter

Incomplete tablets

Machine speed

Number of tablets

Detection, counting

Pilfer-proof

Labeling

Yield


Validation batches Process validation reports should be submitted in the

application for prequalification. Formal studies of production scale batches (not less

than three) are required to identify the critical variables.

Provisional equipment control parameters and the corresponding in-process acceptance criteria must be deduced from the results of experiments with the validation batches.

Critical parameters are to be monitored, non-critical ones should be tested occasionally.


4.5-4.7 Validation policy5. Qualification and validation should not be considered

as one-off exercises. An on-going programme should follow their first implementation and should be based on an annual review.

6. The commitment to maintain continued validation status should be stated in the relevant company documentation, such as the quality manual or validation master plan.

7. The responsibility of performing validation should be clearly defined.


Process approachCONTINUOUS IMPROVEMENT OF THE QUALITY MANAGEMENT SYSTEM

CUSTOMER

REQUIREMENTS

CUSTOMER

SATISFACTION

Management responsibility

Resourcemanagement

Monitoring,improvement

Manufacture ProductInputs


Annual FPP quality review (1) Starting materials used in the product, especially those

from new sources. Critical in-process controls and finished product results. All batches that failed to meet established specification(s). All critical deviations or non-conformances and related

investigations. All changes carried out to the processes or analytical

methods. Marketing Authorisation variations submitted, or granted,

or refused, including those for third country dossiers.


Annual FPP quality review (2) Results of the stability monitoring programme. All quality-related returns, complaints and recalls,

including export only medicinal products. Adequacy of previous corrective actions. For new marketing authorisations, a review of post-

marketing commitments. A list of validated procedures and their revalidation

dates. A list of qualified equipment, support utility systems

and their requalification dates, including calibration programs.


Case summary of 20 batches (1)Statistics Av. wt. mg Dissolution % Assay %

Mean 347,6 99,6 98,2

Median 346,9 100,0 97,5

SD 5,2 2.5 2.2

Range 22.3 10.0 8.8

Minimum 337.0 95.6 95.0

Maximum 359.3 105.6 103.8

Conf. level, 95% 2.4 1.3 1.0

Accept. Crit. 350±5% 75%, 40' 90-110


Case summary of 20 batches (2)

1. Acceptance criteria for assay and dissolution

rate are loose and should be tightened.

2. Potential degradation products were not tested.

3. IPC data were not included in the retrospective

analysis of batch records.

4. Failures were not reported, etc.


4.11 Analytical methods, computers and cleaning procedures

It is of critical importance that particular attention is paid to the validation of analytical test methods, automated systems and cleaning procedures.


AUTOMATED SYSTEMS Protection of records, backups Access controls (use, read, write, execute,

delete, or create) Authentication (user ID and static passwords;

user ID and dynamic passwords; and biometric devices)

Audit-trail controls, and many other issues.


Current WHO GMP

Pro

cess

per

form

ance

Time

1992 version of WHO GMP

Without/before GMPPar

amet

ric re

lease

Problems

Stages of process validation


BEST PROCESS

MINIMUM REQUIRED INPUT

MAXIMUM OUTPUT

AT NO COST TO SOCIETY (industrial safety, labour safety, internal and external environment protection)


Costs of qualityVisible costs, e.g., waste and returned goods

Hidden costs, e.g., wrong decisions, non-competitive manufacturing process,low yield, maintenance, idle machine time, workers attitude, etc.


Main points again High quality FPPs can be manufactured only with

high quality processes under control. Premises, equipment and supporting utilities must

be qualified to operate in validated processes. Testing QC samples of FPPs does not guarantee

the quality of the whole batch, or the batch-to-batch consistency of quality.

Validation activities must be organized (VMP) and documented (protocols, records, reports, etc.)


Main points again Prospective and concurrent validations help to

understand what is critical for quality and shows the level of quality, which can be achieved with the available resources.

Qualification and validation should not be considered as one-off exercises.

Quality of FPPs should be reviewed annually. The best process is the most efficient both from

technical and economic/financial points of view.


Literature Pharmaceutical Process Validation, edited by: R. A.

Nash; Alfred H. Wachter, An International Third Edition, Revised and Expanded, Marcel Dekker, Inc. New York, Basel, Hong Kong (2003).

Marjo-Riitta Helle et al.: A literature review of pharmaceutical process validation, 52 references, Pharmaceutical Technology Europe, August 2003.


THANK YOU

谢谢 !

2005.03.03. Dr. Pogány - WHO, Shanghai 1/58 Workshop on Quality Assurance and GMP of Multisource...

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