Regulatory Requirements on PV (General)

8/11/2019 Regulatory Requirements on PV (General)

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OUTLINE

History

Law and Regulations

Principle

The 3 approaches

Option 1, 2 or 3? PIC/S

Typical Content of Process Validation

Re-validation

Common Mistake P3.4 Process Validation

Guidelines & References


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WHY PV?:- HISTORY

1963 :FD&C were approved; Process Validation has been a legal requirement.


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WHY PV? :- SAMPLING

Pharmaceutical Process Validation 3rdEd. Robert A Nash


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LAW AND REGULATIONS

Poison Act 1952

Sales of Drug Act 1952

Control of Drugs andCosmetics Regulations

1984


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WHAT THE GUIDELINES SAY ON PV?


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PRINCIPLE

a. PIC/S

PI 006-3 (25 September 2007)

6.1 Principle

PV is the means of ensuring, and providing

documentary evidence that processes (within

their specified design parameters) are capableof repeatedly and reliably producing a finished

product of the required quality.


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PRINCIPLE

b. ASEAN Guidelines on Process validation

PV is a means of ensuring that manufacturing

processes are capable of consistently

producing a finished product of the required

quality.

It involves providing documentary evidence

that the key steps in the manufacturing process

are consistent and reproducible.


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PRINCIPLE

c. EMEA

Note for Guidance on Process Validation. (1stMarch2001)

Validation is the act of demonstrating anddocumenting that a procedure operates effectively.

PV is the means of ensuring the providingdocumentary evidence that the processes (withintheir specified parameters) are capable ofconsistently producing a finished product of the

required quality.


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PRINCIPLE

d. CDER: Guideline on General Principles of

Process Validation (May 1987)

PV is establishing documented evidence which

provides a high degree of assurance that a

specific process will consistently produce a

product meeting its pre-determinedspecifications and quality characteristics.


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ALL GUIDELINES AGREED THAT PV MEANS

Process which are Reliable, Repeatable, &under control

Repeatable (Normally 3 consecutivebatches)

Must investigate failures

The rationale should be documented ifexperimental method is changed

document deviations, decisions and reasoning

Does not improve processes

Should not validate bad processes

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Prospective Validation

Concurrent Validation

Retrospective Validation


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PROSPECTIVE VALIDATION

PIC/S: PI 006-3. Clauses

6.3.3: Document elements:

a. A description of the process

b. A description of the experiment.

c. Details of the equipment/facilities to be used (including measuring/recording equipment)

together with its calibration status.d. The variables to be monitored.

e. The samples to be takenwhere when, how and how many.

f. The product performance characteristic/attributes to be monitored, together with the testmethod.

g. The acceptable limits.

h. Time Schedules

i. Personnel responsibilities.

j. Details of methods for recording and evaluating results, including statistical analysis.

6.3.4: - All equipment, the production environment and analytical test methods to be usedhave been fully validated (IQ/OQ).

- Staff have been properly trained.


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PROSPECTIVE VALIDATION. (CONTINUED)

6.3.6: - Sufficient number of runs and observation.

- Generally accept 3 consecutive batches.

6.3.7: - Batches made should be the same size as full scale production.

6.3.8: - Extensive testing should be performed on the product at various stages.- Detailed testing should be done on the final product and its package.

6.3.9: - DOCUMENT it and include it in Validation report!

a. A description of the process.

b. Detailed Summary of results (in-process, final testing, including failed test). Rawdata or reference of sources.

c. Additional work or deviation should be noted and explained.

d. A review and comparison with those expected.

e. Formal acceptance/rejection of the work by the team/persons.


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CONCURRENT VALIDATION

Clause 6.4.4 Documentation requirements are the same as

specified for Prospective Validation

and the testing to be carried out in-process and onthe finished product will be as specified in approvedprotocols.

The completed protocols and reports should bereviewed and approved before product is release forsale or supply.


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CONCURRENT VALIDATION

Acceptable in the case of orphan drugs,

when the number of production batches per

year is expected to be low.

Should seek prior consent from DRA.


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RETROSPECTIVE VALIDATION

Can be performed for existing non-sterileproductswhich already in the market for some time.

Involves trend analysis of Historical manufacturingand QC data.

Must meet following condition.

i. No change in formulation.

ii. No change in manufacturing process or analytical

method.iii. No change in equipment or site(s) of manufacturing

iv. CpK >1.33 based on 1020 batches


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PROCESS VALIDATION CHALLENGES THE

Facility

Environment

Services & Utilities Equipment and machines

Personnel

Standard Procedures and Operatingconditions (the process)

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TYPICAL CONTENT OF PVROBERT A NASH; PHARMACEUTICAL PROCESS VALIDATION 3RDED.

Safety Instruction

Environmental Restriction

Equipment

Raw Materials

Process Flow Charts

Critical Process Parameters & Related means of controls Responsibilities of each participating group

Cleaning validation & verification requirements

Master batch component; percentage by weight

Production batch component

Process batch record

Product testing

Formulation

Validation sampling & testing

Definition of validation criteria.

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ASEAN GUIDELINE:

CONTENT OF VALIDATION (SCHEME)

a) A short Description of the manufacturing process in a schematic

drawing or flow chart.

b) A summary of critical process, control variables and justification for

their selection.

c) Finished Product specification

d) Details analytical methods (reference to the dossier)

e) In process control proposed and with acceptance criteria.

f) Additional testing intended to be carried out (eg with proposed

acceptance criteria and analytical validation appropriate).

g) Sampling Planwhere, when and how samples are taken.

h) Details of method for recording and evaluation of results.

i) Proposed time frames for carrying out the studies.

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ASEAN GUIDELINE:

CONTENT OF VALIDATION (REPORT)

a) Summary

b) Introduction

c) Batches used for Validation

d) Manufacturing Equipment

e) Critical Process Steps and parameters

f) Acceptance criteria.

g) Sampling Plan

h) Tabulation of test results.

i) Batch Analysis

j) Evaluation of Data, and where applicable. Including statisticalprocess control analysis.

k) Evaluation of data including comparison against acceptance criteria.

l) Discussion on deviations and out of specification results.

m) Conclusion and recommendation.

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PROCESS VALIDATION SCHEME

Information RemarkShort description of the Process. -summary of the critical processing steps

-critical parameters to be monitored during

validation.

Finished product specification - release

Details of analytical methods. - References to the dossier

In Process Controls proposed with acceptance

criteria.

Additional testing intended to be carried out. -Proposed acceptance criteria

-Analytical validation

Sampling Plan -Where, when and how the samples are taken.

Details of method for recording and evaluation

of results.

Proposed timeframe


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OPTION (ASEAN GUIDELINES)

Option Documentation

Option 1 i. Validation report for 3 consecutive batches

Option 2 i. Pharmaceutical Development report.

ii. Validation report on 1 pilot batch OR

Validation scheme.iii. Commitment to conduct Validation study.

Option 3 i. Validation document from reference country.

ii. Commitment to conduct validation study.

Pilot Batch:

10% of commercial batch, OR 100,000s OR whichever is higher.

Retrospective:Previous data of 1020 consecutive batches.


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PRE-REQUISITES FOR PROCESS VALIDATION

Facility and controlled environment(s) -

qualified.

Critical services and Utilities - qualified.

Equipment -calibrated and qualified. GMP-related computer system - qualified.

Test method - validated.

Personnel - trained.

Master batch documentation -approved for

use.

Critical process parameters - known and

documented.

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VALIDATION

Exercise 1 You are given a tablet

manufacturing flow chart

to study,.

I. List the critical steps that arerequired to be validated

II. List the critical equipment

required to be qualified

III. Identify the variables and

construct a table as directedIV. Discuss Worst Case scenario

for this process.

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I) CRITICAL STEP

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B) CRITICAL EQUIPMENT

No Equipment Model Type Qualification

Status

1 Granulator MG300 300L DQ-IQ-OQ-PQ

2 Fluidized Bed Dryer FBD01 - DQ-IQ-OQ-PQ

3 Cube Blender CB250 250L DQ-IQ-OQ-PQ

4 Compression CMB4 Rotary 25

station

DQ-IQ-OQ

5 Coater Thai

Coater

60 DQ-IQ-OQ-PQ

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PROCESS VARIABLEINPUT: Critical process

Parameters

Process OUTPUTS: Critical

Quality Attributes

(Variables)

i. Speed,

ii. Fluid amount,

iii. Time,

iv. Sieve Diameter,

Blend & Wt Granulation LODGranules Uniformity

i. Air temp,

ii. Product Temp,

iii. Time

Fluid Bed Dryer Particle sizeLOD

i. Blender dimension,

ii. Speed, load, time,Blending Blend uniformity

Flow properties

i. Comp. Speed,

ii. Force,

iii. Feed rate

Compression Weight controlDisintegration/Hardness,

Assay

Etc,i. Inlet temp,

ii. Bed Temp,

iii. Exhaust Temp.

iv. Coating Pan RPM,

v. Nozzles No.

vi. Spraying rate.

vii. Spray rate,

Coating Appearance,Dimension,

Dissolution rate

Weight,

Hardness

Assay,

Etc.

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C) WORST CASE SCENARIOProcess INPUT: Critical process

Parameters

Min Max

Blend & Wt

Granulation

i. Speed,

ii. Fluid amount,iii. Time,

iv. Sieve Diameter,

200rpm

5L 20minute

300rpm

6L 30 minute

Fluid Bed

Dryer

i. Air temp,

ii. Product Temp,

iii. Time

55-75oC

2hrs

55-75oC

4 hrs

Blendingi. Blender dimension,

ii. Speed, load,

iii. time,

iv. Holding time

5 minute 10 minute

Compression i. Comp. Speed,ii. Force,

iii. Feed rate

iv. Holding time

300rpm

12 tonnes

400rpm

40 tonnes

Coating i. Inlet temp,ii. Bed Temp,

iii. Exhaust Temp.

iv. Coating Pan RPM,

v. Nozzles No.

vi. Spraying rate.

vii. Spray rate,

viii. Holding time

55 deg C

40 rpm

1 Liter per hr.

70 deg C

50 rpm

2 liter per hr

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CHANGE CONTROL RE-VALIDATION

A repeat of the process validation to provide an

assurance that changes in process/equipment

introduced in accordance with change control

procedures do not adversely affect process

characteristics and product quality.

PIC/S Code of GMP Annex 15 Glossary

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RE-VALIDATION DUE TO CHANGES

a) Manufacturing Process Change to Master Processing Instructions (Methods)

b) Formulation Change of Bill of Materials, formulation or batches proportions

Change in raw material suppliers or components

c) Equipment Significant alteration to processing equipment

Introduction of new equipment or utilities

e) Environment Significant change in processing conditions or environment

After extensive preventive or running maintenance work.

f)

Methods & Specifications Major changes in quality control methods or specifications If in-process or quality control results are outside pre-set limits.

If in-process or quality control data indicates a significant process shift or change in processcapability.

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PIC/S PI 006-3 CLAUSE 6.7.4

Changes that are likely to require Re-Validation are as follows:a) Changes of Raw Materials (physical properties such as density,

viscosity, particle size distribution may affect the process or product.

b) Change of starting material manufacturer.

c) Changes of Packaging material (e.g.: substituting plastic for glass).

d) Changes in the process (E.g.: mixing times, drying temperatures),e) Changes in the equipment (E.g.: addition of automatic detection

systems). Changes of equipment which involved the replacement ofequipment on a like for like basis would not normally require re-validation.

f) Production area and support system changes (e.g.: rearrangement of

areas, new water treatment method).g) Transfer of process to another site.

h) Unexpected changes (e.g.: those observed during self inspection orduring routine analysis of process trend data).


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COMMON MISTAKE

Frequency

Criticality

A B

C D


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A) ALWAYS BUT NOT CRITICAL

Type ExampleMissing information. -Pre-requisite status?

-Raw Material, Packaging Material, Equipment,

Facilities, Operators?

-Location & Address,

-Missing pages

-Blur & Low resolution document.

Typo error. -Color description,

-Parameters, (Temp, time, etc)

-Instruction,

Wrong document. -Different strength.-Old processes.

-Old/Different Plant

Incomplete Document -Protocol not submitted

-Report/Summary not submitted


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B) SELDOM AND NOT CRITICAL

Type ExampleSubmitting unnecessary

documents.

-DQ, IQ, OQ.

-Media Fill Report for terminal process.


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C) SELDOM AND CRITICAL

Type Example-Totally different process. -Wet granulation Vs. Dry granulation.

-Different media fill approach

(powder filling vs. liquid filling)

- Poor GMP practices. -Poor aseptic control.

-Renovated plant.

- Unjustified PV approach. - Retrospective or Concurrent instead of Prospective.

- Different Formulation -New formulation.-Different product strength

-Different coating material.

-Different ingredients quantity.


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D) ALWAYS AND CRITICAL

Type Example

-Re-validation condition -

-Inconsistency with proposed

manufacturing process.

- Load, Speed, Temperature, time, distance, holding time,

pressure, etc.

- Undocumented important evidence. -Observed Equipment/process parameters

-In-Process Manufacturing

-Different equipment -Type of blender,

-Load size,

-Single punch vs. Rotary Punch

-Different materials. -Unapproved sources.

-Unapproved Documents. -Signature,

-Conclusion

-Different product Specification - Color, dimension,


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DO CGMPS REQUIRE THREE SUCCESSFUL PROCESS VALIDATION BATCHES BEFORE A NEW ACTIVE

PHARMACEUTICAL INGREDIENT API) OR A FINISHED DRUG PRODUCT IS RELEASED FOR DISTRIBUTION?

Sources: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124782.htm

No. Neither the CGMP regulations nor FDA policy specifies a minimum number of batches to

validate a manufacturing process. The current industry guidance on APIs (see ICH Q7Afor APIs)also does not specify a specific number of batches for process validation.

FDA recognizes that validating a manufacturing process, or a change to a process, cannot bereduced to so simplistic a formula as the completion of three successful full scale batches. Theagency acknowledges that the idea of three validation batches has become prevalent, in partdue to language in its own guidance documents. However, FDA is now clarifying currentexpectations on process validation. The 1987 Guideline of General Principles of ProcessValidationis currently being revised to address this issue. The emphasis for demonstratingvalidated processes is placed on the manufacturers process design and development studies inaddition to its demonstration of reproducibility at scale, a goal that has always been expected.

However, a minimum number of conformance (a.k.a. validation) batchesnecessary to validate the manufacturing processes is not specified.

The manufacturer is expected to have a sound rationale for its choices in thisregard.

The agency encourages the use of science based approaches to processvalidation.
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124782.htmhttp://www.fda.gov/cder/guidance/4286fnl.htmhttp://www.fda.gov/cder/guidance/4286fnl.htmhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124782.htm


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CURRENT & FUTURE?

Cleaning Validation

Computer & Software Validation

Modern Process

Glove Box Isolators

Restricted Access Barrier System (RABs)

Blow, Fill and Seal / Form, Fill & Seal

Robotic controlled

Worldwide Harmonization


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Market holder responsibilities1. Option & Approach selection.

2. Document Submission

3. Details of Validation


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1. OPTION AND APPROACH.

Option ASEAN Guidelines Process Validation Approach

Option 1i. Validation Report for 3 consecutive batches.

Prospective Validation 3 consecutive successful batches or more

Option 2

i. Pharmaceutical Development report.ii. Validation report on 1 pilot batch OR

Validation scheme.

iii. Commitment to conduct Validation study.

Concurrent Validation

3 consecutive batches or more

Option 3i. Validation Document from reference country.

ii. Commitment To conduct Validation Study

Retrospective Validation Previous data of 10-20* consecutive batches

*ASEAN Guidelines On Process validation


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2. DOCUMENT SUBMISSION

Document Checkbox RemarkA Development Pharmaceutical Report Option 2

B Validation Scheme / Protocol

C Validation ReportPilot Batch

Full production batch

Option 2

Option 1

D Supporting documents.

Cleaning validation


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3. DETAILS OF VALIDATION

a) Know your product.

b) Know the Validation details. Approach : Prospective / Concurrent / Retrospective ?.

Product ,

Name,

Strength,

Dosage

Form

Primary

Packing

Proposed

Commercial

Batch size

Manufacturer Country

No Batch

No

Mfg Date Batch Type Validated

Batch Size

Manufacturer Country

Experiment?

Pilot?

Commercial?


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Question:

If the validation data submitted for 3 consecutive production batches

showed that they fully comply with specifications but do not fulfil the

process validation acceptance criteria, would they be approved formarketing?

Answer

The onus is on the manufacturer to ensure that the manufacturing process is

well controlled prior to manufacturing the batches for marketing. The

manufacturer should provide justification for not meeting the acceptance criteria

of process validation and may need to re-validate the process before releasing

the said product batches which meet the quality specification for sale.

Sources:ASEAN Guidelines on Process Validation (Q&A)http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/western_medicines/files

_guidelines.Par.20042.File.dat/ASEAN_Guideline_on_Process_Validation_Q&A_Version2_Jul07.pdf
http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/western_medicines/files_guidelines.Par.20042.File.dat/ASEAN_Guideline_on_Process_Validation_Q&A_Version2_Jul07.pdfhttp://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/western_medicines/files_guidelines.Par.20042.File.dat/ASEAN_Guideline_on_Process_Validation_Q&A_Version2_Jul07.pdfhttp://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/western_medicines/files_guidelines.Par.20042.File.dat/ASEAN_Guideline_on_Process_Validation_Q&A_Version2_Jul07.pdfhttp://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/western_medicines/files_guidelines.Par.20042.File.dat/ASEAN_Guideline_on_Process_Validation_Q&A_Version2_Jul07.pdf


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REFERENCES

A) PIC/S: http://www.picscheme.org

e.g.: i) PI 006-3 : Recommendations on Validation Master Plan Intallation and OperationalQualification Non Sterile Process Validation Cleaning validation

ii) PI 007-1: Recommendation on Validation of Aseptic Processes

iii) PI 009-8 (Annexes)

B) EMEA: http://www.tga.gov.au/docs/html/euguide/euad_qual.htm#qualitymedicinal

e.g.: i) Note for Guidance on Process validation

C) Singapore (HSA):

http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/GMP/guidelines.html

e.g.: i) Non Sterile Process Validation

ii) Validation of Aseptic Process iii) Validation of Terminal Moist Heat Sterilization
http://www.picscheme.org/http://www.tga.gov.au/docs/html/euguide/euad_qual.htmhttp://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/GMP/guidelines.htmlhttp://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/GMP/guidelines.htmlhttp://www.tga.gov.au/docs/html/euguide/euad_qual.htmhttp://www.picscheme.org/


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REFERENCES

D) ASEAN: http://www.bpfk.gov.my/

E.g.: i) ASEAN Guideline on Process Validation (29 KB)ii)ASEAN Guideline on Process Validation Q&A

http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.html

E) FDA/CDER

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064971.htm

eg: i) General Principles of Process Validation

ii) Sterile Drug Products Produced by Aseptic Processing - cGMP

F) International Conference on Harmonisation - Quality (ICH-Q)

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005.htm

eg: i) Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients

ii) Q8(R1) Pharmaceutical Development Revision 1

iii) Q9 Quality Risk Management

iv) Q10 Pharmaceutical Quality System

G) Global Harmonization task Force
http://www.bpfk.gov.my/http://202.144.202.76/bpfk/view_file.cfm?fileid=204http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/western_medicines/files_guidelines.Par.20042.File.dat/ASEAN_Guideline_on_Process_Validation_Q&A_Version2_Jul07.pdfhttp://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.htmlhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064971.htmhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064971.htmhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005.htmhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005.htmhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073497.pdfhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073507.pdfhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073511.pdfhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073517.pdfhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073517.pdfhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073511.pdfhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073511.pdfhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073507.pdfhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073497.pdfhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005.htmhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005.htmhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064971.htmhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064971.htmhttp://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/western_medicines/guidelines.htmlhttp://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/western_medicines/files_guidelines.Par.20042.File.dat/ASEAN_Guideline_on_Process_Validation_Q&A_Version2_Jul07.pdfhttp://202.144.202.76/bpfk/view_file.cfm?fileid=204http://202.144.202.76/bpfk/view_file.cfm?fileid=204http://202.144.202.76/bpfk/view_file.cfm?fileid=204http://www.bpfk.gov.my/


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