Review of Control Strategy of GMP

Obaid Ali & Roohi B. Obaid (March 2013)

Disclaimer and References

The views expressed in this presentation are not necessarily of the Drug Regulatory Authority of Pakistan

It is an informal communication that represents the best current judgment and does not constitute an advisory opinion or binding or otherwise obligate or commit the DRAP, to the views expressed.

This presentation is designed by the speaker after consulting international reference documents

Presentation Focus

Cont’d

Presentation Focus

Back mirror challenges; Wake up call….s

Regulatory Complexity

Why Regulations?

Its not just as simple as its seems to be

Pre-approval Inspection

Post-approval Inspection

Pre-market Review

Post-market Review

SCENE

Regulatory Background

D R U

G

SCENE

Very near to your and your beloved one’s lives

Very near to your and your beloved one’s lives

Health care profession and business

Health care profession and business

Regulations

protect

and

promote

Public Health

New

Generics

Primary Logical Boundaries

D R U G S

New Drugs

Main Concerns

Safety

Effi

cacy

Clinical SitesS

uppl

y C

hain Vigilance

Manufacturing Site

1

Main Elements of Review Process for New Drugs

Toxicology & Pharmacology

Clinical Pharmacol & Bio-Pharmaceutics

Medical & StatisticalImmunological review esp. for BiologicalsChemistry & CMC

Risk Evaluation & Mitigation Strategy

234

56

SCENE

5

Cross Discipline7

CONCERNS

CMC review….. SMF, DMF, LIF………..CMC review….. SMF, DMF, LIF………..

SCENE

Generic or

approved

new Drug

for new site

New Drug

Main Elements of Review Process for Generic Drugs

Clinical study….Bio-studies….Dissolution studies………Justification of waiverClinical study….Bio-studies….Dissolution studies………Justification of waiver

Labeling review……Product Development……Stability……..Shelf lifeLabeling review……Product Development……Stability……..Shelf life

Manufacturing capacity………Pre-approval Inspection report………..history of GMPManufacturing capacity………Pre-approval Inspection report………..history of GMP

Review Journey

ProcessDesign

Review

SCENE

Mee

tings

Writing

SCENE

Review Model of the 21st Century

CTD International

Conference on Harmonization

Question based review

Main Challenges

ABILITY

Data Analysis and Assessment

SCENE

Iden

tific

atio

n of

Dat

a G

enui

nene

ss

Report W

riting

Consistency, mix-up, Contamination, Cross-contamination, Traceability and Data Integrity

Quality can not be observed by every one and/or by naked eye or even by product testing.

………………..triggered a serious adverse reaction by depositing itself in the bone marrow and ending the body's resistance. The generation of white blood cells stopped in the body. Among the symptoms of the disease were change in skin color/pigmentation, low platelet count and blood vomiting.

………………..triggered a serious adverse reaction by depositing itself in the bone marrow and ending the body's resistance. The generation of white blood cells stopped in the body. Among the symptoms of the disease were change in skin color/pigmentation, low platelet count and blood vomiting.

Recall the painful memories

Good Manufacturing Practice is the only and absolute answer to

ensure product quality of drug for approved drugs

Good Manufacturing Practice is the only and absolute answer to

ensure product quality of drug for approved drugs

Regulatory Mandate

………GMP under Schedule B……..

Obligatory to comply

Regulatory Mandate

………GMP under Schedule B……..

Obligatory to comply

GMP Expectations

Is the drug consistent to each other

Is it mix up free

Is it not contaminated

Is it not cross-contaminated

Is data and manufacturing history traceable

Is data reliable and genuine...........

Variations play ?????

Variations play ?????

Mix-upA number of drug products are being manufactured in a

same manufacturing facility

Label mix upPowder mix upBulk product mix upIn-process mix upBlister mix up Etc.

Let’s make science visible

Case Studies

Unknown peak in Misoprostol

Unknown peak identified in 13 lots of Cytotec tablet

A delayed (after 1.5 months) internal investigation report suggested contamination

during handling but it was unknown contaminant

Investigation Failure at QCU

Another investigation after 1.5 years suggested (based on relative retention time) the unknown

contaminant as toluene

Investigation Failure at QCU

After 1.5 years internal evaluation revealed the probable source of toluene was related to loose ink

in blister packaging line

Firm did not considered it as a foreign substance and argued that toluene is also used in chemical

synthesis of misoprostol oil. It was a hypothesis, no record was available

Investigation Failure at QCU

Not a single cause out of both could be assigned, whether it was a residue from API or improper

packaging

There was no evidence that toluene is being monitored during the stability of API

Not a single cause out of both could be assigned, whether it was a residue from API or improper

packaging

There was no evidence that toluene is being monitored during the stability of API

Investigation Failure at QCU

Diethylphthalate (DEP) can be a source of contamination from desiccant cartridge

J&JDec 2009

Several complaints of uncharacteristic strong odor were received to J&J from 2008 to 2009 for their several OTC products packaged in bottles.

J&J failed to conduct a timely, comprehensive investigation, determine and assign a root cause

J&JDec 2009

The adverse event was reported as gastrointestinal distress

This lead to recall of several lots of Tylenol Arthritis Relief Caplets and several other OTC

products

J&JDec 2009

The reason was a pesticide 2,4,6 Tribromophenol (TBP) sprayed on wooden

pallets used to keep finished products during shipping

This pesticide degraded to 2,4,6 Tribromoanisole (TBA) with a musty odor

contaminating product containers and finished product in those containers

Pfizer 2010Pfizer 2010

Several lots of Lipitor (191, 000 bottles)were recalled due to the same reason. i.e. unusual odor/ moldy smell of 2,4,6 Tribromoanisole, a degradant of TBP used to disinfect wooden

pallets

Several lots of Lipitor (191, 000 bottles)were recalled due to the same reason. i.e. unusual odor/ moldy smell of 2,4,6 Tribromoanisole, a degradant of TBP used to disinfect wooden

pallets

GSK June 2011GSK June 2011

A huge recall of Augmentin syrup in China, Hong Kong etc. contaminated with di-isodecyl

phthalate (DIDP) Plasticizer ordered by Chinese SFDA

A huge recall of Augmentin syrup in China, Hong Kong etc. contaminated with di-isodecyl

phthalate (DIDP) Plasticizer ordered by Chinese SFDA

GSK June 2011GSK June 2011

According to Chinese SFDA, the drug was tainted with the DIDP plasticizer which is used

to make the plastic more flexible

ResultA huge number of bottles were recalled

According to Chinese SFDA, the drug was tainted with the DIDP plasticizer which is used

to make the plastic more flexible

ResultA huge number of bottles were recalled

Ranbaxy 2008Batamandi

Ranbaxy 2008Batamandi

Cleaning record of the equipment V-blender contained signature of employees who

verified the cleaning of equipment, but were not actually present at that particular time

Cleaning record of the equipment V-blender contained signature of employees who

verified the cleaning of equipment, but were not actually present at that particular time

Ranbaxy 2008Batamandi

Ranbaxy 2008Batamandi

This came to bright through security log records used to control the entry of all

personnel entering or exiting the facility

This came to bright through security log records used to control the entry of all

personnel entering or exiting the facility

Ranbaxy 2008Batamandi

Ranbaxy 2008Batamandi

The security log records showed that the persons/supervisors who signed the “Checked by Production Executive or

“Cleared by QA Executive” were not present at the facility on the days equipment was

cleaned

The security log records showed that the persons/supervisors who signed the “Checked by Production Executive or

“Cleared by QA Executive” were not present at the facility on the days equipment was

cleaned

Ranbaxy 2008Batamandi

Ranbaxy 2008Batamandi

Furthermore, the employee of the firm believed that his physical presence was not necessary

during the activity and he can sign off by asking someone to bring records to him for signature on the batch records as to have checked the

activity

Furthermore, the employee of the firm believed that his physical presence was not necessary

during the activity and he can sign off by asking someone to bring records to him for signature on the batch records as to have checked the

activity

Ranbaxy 2008Batamandi

Ranbaxy 2008Batamandi

This demonstrates the lack of understanding of the fundamental purpose of independent

verification under cGMP. Such verification is paramount to ensure that

procedures or works are adequately performed to reduce the risk of human error

This demonstrates the lack of understanding of the fundamental purpose of independent

verification under cGMP. Such verification is paramount to ensure that

procedures or works are adequately performed to reduce the risk of human error

Ranbaxy 2008Batamandi

Ranbaxy 2008Batamandi

Incomplete or compromised cleaning of equipment can provide a way for cross-

contamination or inadvertent contamination of drug products with residual cleaning agents

or solvents

Incomplete or compromised cleaning of equipment can provide a way for cross-

contamination or inadvertent contamination of drug products with residual cleaning agents

or solvents

Ranbaxy 2008Batamandi

Ranbaxy 2008Batamandi

The deficiencies in equipment cleaning and batch production and control records threaten the concerns related to the

conduct, adequacy and oversight of Quality System of the firm especially the integrity

and reliability of records

The deficiencies in equipment cleaning and batch production and control records threaten the concerns related to the

conduct, adequacy and oversight of Quality System of the firm especially the integrity

and reliability of records

Ranbaxy 2008 Dewas

Ranbaxy 2008 Dewas

Persons from QC moved freely collecting samples between beta-lactam and non-beta-

lactam manufacturing blocks

Persons from QC moved freely collecting samples between beta-lactam and non-beta-

lactam manufacturing blocks

Ranbaxy 2008 Dewas

Ranbaxy 2008 Dewas

Persons working in beta-lactam API warehouses were moving freely on the

manufacturing campus

Persons working in beta-lactam API warehouses were moving freely on the

manufacturing campus

Ranbaxy 2008 Dewas

Ranbaxy 2008 Dewas

Persons working in beta-lactam API warehouses were moving freely on the

manufacturing campus

Persons working in beta-lactam API warehouses were moving freely on the

manufacturing campus

Ranbaxy 2008 Dewas

Ranbaxy 2008 Dewas

Persons working in Cephalosporin API dispensing area were observed with powder on their gowns and coming in direct contact

with outer surface of a bulk material bag that was placed on transport equipment that can

enter in non-beta-lactam areas

Persons working in Cephalosporin API dispensing area were observed with powder on their gowns and coming in direct contact

with outer surface of a bulk material bag that was placed on transport equipment that can

enter in non-beta-lactam areas

Ranbaxy 2008 Dewas

Ranbaxy 2008 Dewas

Surface monitoring (sampling/testing) for residual traces of penicillin type beta-lactams is

not performed in the Penem Block where penem sterile parenterals are manufactured or in Block where multiple cephalosporin finished

products are manufactured.

Surface monitoring (sampling/testing) for residual traces of penicillin type beta-lactams is

not performed in the Penem Block where penem sterile parenterals are manufactured or in Block where multiple cephalosporin finished

products are manufactured.

Ranbaxy 2008 Dewas

Ranbaxy 2008 Dewas

Surface monitoring for residual traces of cephalosporin type beta-lactams is not performed in the General Block where

multiple non-beta-lactam finished products are manufactured or in the Penem Block

where sterile parenterals are manufactured.

Surface monitoring for residual traces of cephalosporin type beta-lactams is not performed in the General Block where

multiple non-beta-lactam finished products are manufactured or in the Penem Block

where sterile parenterals are manufactured.

Ranbaxy 2008 Dewas

Ranbaxy 2008 Dewas

Result of such observationsConsent Decree and Import Alert for their

products in USA until drugs can be manufactured in the facilities complying with US manufacturing

Quality Standards

Result of such observationsConsent Decree and Import Alert for their

products in USA until drugs can be manufactured in the facilities complying with US manufacturing

Quality Standards

Human Factor Analysis and Classification System

What considerations will enhance preventive system and control?

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

Human Factor Analysis & Classification System (HFACS)

“………records are not completed

contemporaneously”

“………records are not completed

contemporaneously”

Misguided

Malicious

Closing Message SCENE

If there is a will, there is a way

If everyone is moving forward together, then success takes care of itself

(Henry Ford)

If everyone is moving forward together, then success takes care of itself

(Henry Ford)

oarohama@gmail.com