GMP Systems Integration–Combine Results and Utilize as a Compliance Tool

Betzaida Bigio 1

GMP SYSTEMS INTEGRATION –COMBINE RESULTS AND UTILIZE AS A COMPLIANCE TOOL

Betzaida BigioBristol Myers - Squibb

We will be Discussing

GMP systems – no definitions

How they interact

Review of recent observations

How they can be integrated to establish controls

Interactive Exercise

Betzaida Bigio 2

Annual Product Reviews (APR) Change Control Validations Equipment qualifications Vendor Qualifications Preventive Maintenance (PM’s) Audits (Internal & External) Suppliers audits Stability Customer complaints Suppliers complaints CAPA Investigations

8/30/2012 3

GMP Systems

Discussion of Recent observations

Classification of observation

Integration between systems based on each observation

8/30/2012 4

Integration Between Systems

Discussion of 2011- 2012 Warning letters Eighteen (18) Warning letters Focused on Pharmaceutical Industries cGMP for API (Active Pharmaceutical Ingredient) cGMP for Finished Pharmaceutical Location of inspected Sites:

India China Germany Poland UK Canada Mexico Switzerland Israel Japan US

8/30/2012 5

Recent Health Authorities Findings

Recent Observations - “Hot” Topics Cleaning Validation

Investigations

Media Fill

Laboratory Controls

Test Methods

Environmental Monitoring

Microbiology Contamination Prevention

Disinfectant qualification

Visual Inspection Qualification

Supplier Qualification

Reduce testing

APR, Record Retention

Incoming testing of raw materials8/30/2012 6

Cleaning Validation

Use of two equipment parts for the production of multiple drug products without validating the process

Process validation for six (6) products conducted only with one out of two parts

Parts identical in construction but different internal configurations

Failure to demonstrate are identical

Not cleaned and maintained equipment at appropriate intervals – holding time

8/30/2012 7

Integration Between Systems per Observation

Validation/Qualification: Controls

Use of two equipment parts for the production of multiple drug products without validating the process Process validation for six (6)

products conducted only with one out of two parts

Parts identical in construction but different internal configurations

Failure to demonstrate are identical

Not cleaned and maintained equipment at appropriate intervals –holding time

Equipment qualification

Process Validation

Cleaning validation

Holding time

Dirty time

Systems: Change Control

Validation

8/30/2012 8

Cleaning Validation

Failure to have in shared manufactured areas, multi-product equipment:

Well-designed contamination prevention strategy in place

Proper segregation

Or dedicated equipment to a single mfg process

No documented evidence of cleaning between batches or between product changeovers occurred on non-dedicated equipment

Technology transfer to a facility that was previously used to manufacture without conducting adequate decontamination, renovation, and activation of the facility

8/30/2012 9


Validations/Qualifications: Controls

Failure to have in shared manufactured areas, multi-product equipment:

Well-designed contamination prevention strategy in place

Proper segregation Or dedicated equipment to a

single mfg process

No documented evidence of cleaning between batches or between product changeovers occurred on non-dedicated equipment

Technology transfer to a facility that was previously used to manufacture without conducting adequate decontamination, renovation, and activation of the facility

Equipment qualification

Process Validation

Cleaning validation

Holding time

Dirty time

Systems: Change Control

Validation

8/30/2012 10

Investigations

Not thoroughly investigated the failure of a batch or any of its components

Failure to include other batches in investigations

No investigation raw data for a media fill failure

Failure to determine root cause on crystals in the vial

Changes to filling process

Changes to filling needles

Vial washers

8/30/2012 11


Investigations: Controls

Not thoroughly investigated the failure of a batch or any of its components

Failure to include other batches in investigations

No investigation raw data for a media fill failure

Failure to determine root cause on crystals in the vial Changes to filling process Changes to filling needles Vial washers

Product behavior on APR

Stability

Predictive maintenance

Preventive maintenance

Systems: Investigations

CAPA

Supplier

Change Control

PM’s

8/30/2012 12

Investigations

Investigations Failure to investigate and document contamination

of API Root cause not determined and production continued

No segregation of impacted lots

Failure to extend investigation to other batches

Contaminated lot release and shipped, then recalled –failure to have controls in place to identify material status

Inadequate equipment maintenance program Firm authorize the use of equipment known to be

defective (10 maintenance requests in one year)8/30/2012 13


Investigations: Controls

Failure to investigate and document contamination of API Root cause not determined and

production continued No segregation of impacted lots Failure to extend investigation to

other batches Contaminated lot release and

shipped, then recalled – failure to have controls in place to identify material status

Inadequate equipment maintenance program Firm authorize the use of

equipment known to be defective (10 maintenance requests in one year)

Product behavior on APR

Stability

Materials segregation

Supplier’s audit

Preventive & Predictive maintenance

Systems: Investigations CAPA Supplier Change Control Materials PM’s

8/30/2012 14

Media Fill

Media fill insufficient to establish that the aseptic process is in control

Inadequate reconciliation of filled vials

Filled vials not match with incubated vials

Employee who perform critical duties in your aseptic process did not participate in the simulation process qualification

8/30/2012 15


Media Fill: Controls

Media fill insufficient to establish that the aseptic process is in control Inadequate reconciliation of

filled vials Filled vials not match with

incubated vials Employee who perform

critical duties in your aseptic process did not participate in the simulation process qualification

Manufacturing simulation

QC – Microbiology

Training – Job description, job duties, SOP’s, employee qualifications, and certifications aligned

Systems: Manufacturing

Training

QC - Microbiology

8/30/2012 16

Laboratory Controls

Test Methods

Not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures design to assure that components, in-process materials, and DP conforms with standards

Validation data for laboratory methods incomplete or not available

Validation method approved without the complete data in place

Equipment qualification – all instruments whether newly purchased or already in use , be qualified prior to being release for use

8/30/2012 17


Laboratory Controls: Controls

Test Methods Not established scientifically sound

and appropriate specifications, standards, sampling plans, and test procedures design to assure that components, in-process materials, and DP conforms with standards Validation data for laboratory

methods incomplete or not available

Validation method approved without the complete data in place

Equipment qualification – all instruments whether newly purchased or already in use , be qualified prior to being release for use

8/30/2012 18

Change Control should establish specific requirements

Appropriate equipment qualification

Documentation approval

Employee training

Systems: Quality Assurance

Quality Control

Change Control

Validations/Qualification

Training

Suppliers Qualification

Reduce testing

Inadequate sampling process if no evidence of vendor sampling, shipping, and transit process

Incoming testing of raw materials

Not conducted at least one specific identification test

Lack of appropriate validation of the supplier test result

Accept CoA of a stopper supplier without conducting adequate vendor qualification

No evidence of how your vendor conducts the sampling (composite, segregation…)

8/30/2012 19


Supplier’s Qualification: Controls

Reduce testing Inadequate sampling process if

no evidence of vendor sampling, shipping, and transit process

Incoming testing of raw materials Not conducted at least one

specific identification test Lack of appropriate validation of

the supplier test result Accept CoA of a stopper supplier

without conducting adequate vendor qualification

No evidence of how your vendor conducts the sampling (composite, segregation…)

Material qualification Supplier audit

Quality agreement

Testing of components & material

Comparison between CoA and test results


Quality Control

8/30/2012 20

Shutdown/Start-up

Inadequate aseptic and support area sanitization following maintenance shutdown

Assure to complete:

Media fill

Smoke studies

QA authorization to resume activities

NO failure on Media fill results (this was the case in the warning letter, two contaminated units, not adequate investigated root cause)

8/30/2012 21


Shutdown/Start-up: Controls

Inadequate aseptic and support area sanitization following maintenance shutdown NO failure on Media fill

results (this was the case in the warning letter, two contaminated units, not adequate investigated root cause)

Cleaning

Change Control should establish specific requirements

Asceptic Techniques

Assure to complete: Media fill Smoke studies QA authorization to

resume activities

Systems: Quality Assurance Quality Control Manufacturing

8/30/2012 22


Disinfectant qualification

Not establish a schedule for the cleaning with agent design to kills spores – mold found

Disinfectant rotation – efficacy studies not completed for three of the disinfectant

Failed to demonstrate that is suitable and effective to remove microorganism from different surfaces

Failure to challenge with multiple organisms

8/30/2012 23


Microbiology Contamination Prevention: Controls

Disinfectant qualification Not establish a schedule for the

cleaning with agent design to kills spores – mold found

Disinfectant rotation – efficacy studies not completed for three of the disinfectant

Failed to demonstrate that is suitable and effective to remove microorganism from different surfaces

Failure to challenge with multiple organisms

8/30/2012 24

Quality Control – Micro

Robust Qualification of disinfectant


Quality Control

Qualification


Smoke studies

No evidence of smoke studies

Failure to demonstrate that appropriate design & controls are in place to prevent turbulence and stagnant air in critical areas

8/30/2012 25



Smoke studies

No evidence of smoke studies

Failure to demonstrate that appropriate design & controls are in place to prevent turbulence and stagnant air in critical areas

8/30/2012 26

Robust Smoke studies

Air velocities/pressure & air changes data

Multidisciplinary team to evaluate smoke studies


Quality Control

Engineering

Microbiology Contamination Prevention Environmental Monitoring (EM)

Poor routine examination of facilities (mold in class 100 production

Poor condition of walls

Poor aseptic techniques

Personnel sampling areas (hands, chest, gowning, hood, goggles, sleeves)

Gowned employee not monitored by a second qualified person

EM performed at the end of the shift

Operators sanitizing his hands immediately prior to conducting his own personnel monitoring sampling

Operator spraying his hands directly over the air viable microbial plate. Results may not reflect microbiology environment of the class 100 room.

8/30/2012 27



Environmental Monitoring (EM) Poor routine examination of facilities

(mold in class 100 production Poor condition of walls Poor aseptic techniques

Personnel sampling areas (hands, chest, gowning, hood, goggles, sleeves)

Gowned employee not monitored by a second qualified person

EM performed at the end of the shift Operators sanitizing his hands

immediately prior to conducting his own personnel monitoring sampling

Operator spraying his hands directly over the air viable microbial plate. Results may not reflect microbiology environment of the class 100 room.

8/30/2012 28

Aseptic techniques

Personnel training and qualification

Engineering controls

Facilities walk tru

Internal audits

Preventive maintenance

Systems: Quality Assurance Quality Control Engineering Internal audits Training


Environmental Monitoring (EM)

EM trends not analyzed – failure to address increased adverse trends observed

Not establish a schedule for the cleaning with agent design to kill spores although mold was detected in class 10,000 area

8/30/2012 29



Environmental Monitoring (EM) EM trends not analyzed

– failure to address increased adverse trends observed Not establish a schedule

for the cleaning with agent design to kill spores although mold was detected in class 10,000 area

8/30/2012 30

Aseptic techniques


APR


Quality Control

Training

Visual Inspection Qualification Defect in include visual inspection program

Inspectors qualification failure

Visual inspection certification program does not adequately challenge the technician performing the inspection

SOP should include all possible defects- inspector should be capable to detect all possible critical defects, challenge vial selected, and rotated to ensure that each inspector is challenged to detect each critical defect

8/30/2012 31


Visual Inspection Qualification: Controls

Defect in include visual inspection program

Inspectors qualification failure Visual inspection certification

program does not adequately challenge the technician performing the inspection

SOP should include all possible defects- inspector should be capable to detect all possible critical defects, challenge vial selected, and rotated to ensure that each inspector is challenged to detect each critical defect

8/30/2012 32

Visual Inspection Certification Program



Qualification

Training

Manufacturing

APR & Record Retention

APR

Quality Unit does not perform an annual evaluation of the process

This is the process to assure that changes were effective and the process remains in a validated state

Record Retention

Records destroyed

No evidence of qualification and validation records resulted in a not validated process, and/or not qualified equipment

8/30/2012 33


APR/Record Retention: Controls

APR Quality Unit does not perform

an annual evaluation of the process This is the process to assure that

changes were effective and the process remains in a validated state

Record Retention Records destroyed No evidence of qualification

and validation records resulted in a not validated process, and/or not qualified equipment

8/30/2012 34

APR program in place

Record Retention based on criticality and risk

Change controls, Qualifications/validations -never are destroyed


APR

Validation

Record Management

Interactive Exercise

8/30/2012 35

Instructions

Evaluate recent Observations to different systems and relate each of different GPM Systems

Identify your opportunities

Identify controls that should be in place in each system to avoid the out of compliance situation and establish communication among them

Assure that your control address post implementation sustainability

Identify & avoid Road blocks to maintain compliance

8/30/2012 36

8/30/2012

3

7

Checklist.doc

8/30/2012

3

8

Checklist.doc

GMP Systems Integration–Combine Results and Utilize as a Compliance Tool

Health & Medicine

failure failure

failure systems

controls failure

cleaning validation

equipment parts

components failure

aprthe failure

use of equipment