understanding of product & process for installation of appropriate controls (12 april 2017)

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Understanding of Product & Process For Installation of Appropriate Controls Roohi B. Obaid, R. Ph. Civil Services Officer Member ISPE & PDA 12 April 2017

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Page 1: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Understanding of Product & Process

For Installation of Appropriate Controls

Roohi B. Obaid, R. Ph.Civil Services Officer

Member ISPE & PDA

12 April 2017

Page 2: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

D

I

S

C

L

A

I

M

E

R

Not the view of DRAP

Current judgment

No obligation on DRAP

Regulatory experience

This presentation discusses science and has nothing to do with

any commercial Product.

Page 3: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Why How

Page 4: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Why Howe.g. Saxagliptin

Page 5: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Lets have a look & walk through real cases

Page 6: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

05 Feb 2017

Bupripion HCl ER

Page 7: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

2.7 lakh bottle

Dissolution failure

At 18 month of

stability

Page 8: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Does anybody want to see such news early morning?

Page 9: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Does anybody want to see such news early morning?

Are you confident it will not happen with you?

Page 10: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Does anybody want to see such news early morning?

Are you confident it will not happen with you?

Don’t assume but

keep respecting

science

Page 11: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Does anybody want to see such news early morning?

Are you confident it will not happen with you?

Don’t assume but

keep respecting

science

Understand your

product &

process

Page 12: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Does anybody want to see such news early morning?

Are you confident it will not happen with you?

Don’t assume but

keep respecting

science

Understand your

product &

process

Before it

happens

Page 13: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Drug assay is

compliant

Page 14: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Drug assay is

compliant

Drug is not available

for absorption

Page 15: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Drug assay is

compliant

Drug is not available

for absorption

Do you expect

effect?

Page 16: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Therapeutic

effect under

question

Page 17: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Therapeutic

effect under

questionDisease may progress

Page 18: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Therapeutic

effect under

questionDisease may progress

A series of

consequences

may emerge

Page 19: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Therapeutic

effect under

questionDisease may progress

A series of

consequences

may emerge

Page 20: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Therapeutic

effect under

questionDisease may progress

A series of

consequences

may emerge

Pain killers

Page 21: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Therapeutic

effect under

questionDisease may progress

A series of

consequences

may emerge

Pain killers Cardiac drug

Page 22: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Therapeutic

effect under

questionDisease may progress

A series of

consequences

may emerge

Pain killers Cardiac drug Anti epileptic drug

Page 23: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

2013

Amidate Injection

(Etomidate)

Page 24: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Degradation during

stability

Hospira & Pfizer product

Page 25: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Top Reasons for Recalls

Page 26: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

1

Super or sub potent formulations

Digoxin (double

thickness)

Actavis 2008

Page 27: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

1

Super or sub potent formulations

Digoxin (double

thickness)

Actavis 2008Poor Manufacturing Control

Page 28: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

1

Super or sub potent formulations

Morphine (double size)

KV Pharmaceuticals 2008

Company closed because

they knew the problem &

failed to inform FDA

Fine of 27.6 million USD

Page 29: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

1

Super or sub potent formulations

Morphine (double size)

KV Pharmaceuticals 2008

Company closed because

they knew the problem &

failed to inform FDA

Fine of 27.6 million USD

Poor Manufacturing Control

Page 30: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

2

Particulate Contamination

Takeda, Millenium &

Janssen anti-cancer product

Particulates were seen after

reconstitution

Europe, America & Asia

Polyester like material

originated from filtration

system

Page 31: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

2

Particulate Contamination

Takeda, Millenium &

Janssen anti-cancer product

Particulates were seen after

reconstitution

Europe, America & Asia

Polyester like material

originated from filtration

system

Wrong sort of container used

to store highly acidic or

basic solution

Page 32: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

2

Particulate Contamination

Takeda, Millenium &

Janssen anti-cancer product

Particulates were seen after

reconstitution

Europe, America & Asia

Polyester like material

originated from filtration

system

Glass, silicon & stainless steel …. …in the

glass used to manufacture vials and other

containers.

wear and tear of machinery, abrasion of

stoppers and plungers …in the glass used to

manufacture vials and other containers.

Page 33: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

2

Particulate Contamination

Takeda, Millenium &

Janssen anti-cancer product

Particulates were seen after

reconstitution

Europe, America & Asia

Polyester like material

originated from filtration

system

Inadequate understanding of

the product and process

Page 34: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

3

API’s Contamination

Bulk heparin in China

Over sulfated Chondroitin

Sulfate

80 deaths in USA alone

Found deliberated &

economically motivated

Page 35: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

3

API’s Contamination

Bulk heparin in China

Over sulfated Chondroitin

Sulfate

80 deaths in USA alone

Found deliberated &

economically motivated

Weak supply chain

Unknown contaminant later

named OSCS

Page 36: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

3

API’s Contamination

GSK Worthing UK facility

July 2015

Bactobran cream

containing Mupirocin

recalled

Page 37: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

3

API’s Contamination

GSK Worthing UK facility

July 2015

Bactobran cream

containing Mupirocin

recalled

API Mupirocin

contaminated with penicillin &

foreign substances during Mfg

process

Page 38: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

3

API’s Contamination

GSK Worthing UK facility

July 2015

Bactobran cream

containing Mupirocin

recalled

Inadequate Controls to

Prevent contamination

Page 39: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

3

API’s Contamination

Attix Pharmaceuticals

Canada (April 2015)

A Repackager recalled

hundreds of bulk API

cross-contaminated by

penicillin

Failed to use separate

facilities or equipments

Page 40: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

3

API’s Contamination

Attix Pharmaceuticals

Canada (April 2015)

A Repackager recalled

hundreds of bulk API

cross-contaminated by

penicillin

Failed to use separate

facilities or equipments

Inappropriate practice during operations

Personnel & material movement, use of

non-dedicated facilities

Page 41: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

3

API’s Contamination

Attix Pharmaceuticals

Canada (April 2015)

A Repackager recalled

hundreds of bulk API

cross-contaminated by

penicillin

Failed to use separate

facilities or equipments

Cleaning is not

a substitute for

segregation

Page 42: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

3

API’s Contamination

Attix Pharmaceuticals

Canada (April 2015)

A Repackager recalled

hundreds of bulk API

cross-contaminated by

penicillin

Failed to use separate

facilities or equipments

Cleaning is not

a substitute for

segregation

No safe level of

penicillin

contamination has

been determined to

be a tolerable risk

Page 43: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

3

Contamination

Misoprostol Pharmacia

Peak gave signal but

ignored (13 lots)

Later contaminant

identified to be toluene

Page 44: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

3

Contamination

Misoprostol Pharmacia

Peak gave signal but

ignored (13 lots)

Later contaminant

identified to be toluene

Loose ink in blister packaging line

Page 45: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

3

Contamination

Misoprostol Pharmacia

Peak gave signal but

ignored (13 lots)

Later contaminant

identified to be toluene

Loose ink in blister packaging line

Diethylphthalate (DEP) … from

desiccant cartridge

Page 46: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

3

Contamination

Misoprostol Pharmacia

Peak gave signal but

ignored (13 lots)

Later contaminant

identified to be toluene

Loose ink in blister packaging line

Diethylphthalate (DEP) … from

desiccant cartridge

Cause could not be assigned

whether a residue from API or

improper packaging ….

Page 47: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

4

Sterility Failure

Various drugs for potential

sterility failure found

contaminated with

pathogenic organisms

High threat for HIV, Cystic

Fibrosis or TB

Page 48: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

4

Sterility Failure

Various drugs for potential

sterility failure found

contaminated with

pathogenic organisms

High threat for HIV, Cystic

Fibrosis or TB

Poor manufacturing & environmental

control

Page 49: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

5

Contamination with TBA

Bad odour in product

J&J 2009

Pfizer 2010

TBP, a wood preservative

for pallets converted to

TBA giving bad odour

Page 50: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

5

Contamination with TBA

Bad odour in product

J&J 2009

Pfizer 2010

TBP, a wood preservative

for pallets converted to

TBA giving bad odour

Poor control and desensitized alarms,

throwing away of wake up calls, ended

up with largest recall

Page 51: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

6

Disintegration Failure

Soft gel capsule failed in

disintegration

Millions of capsules

recalled

Company shut down for

a long time

Page 52: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

6

Disintegration Failure

Soft gel capsule failed in

disintegration

Millions of capsules

recalled

Company shut down for

a long time

Page 53: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

6

Dissolution failure

100’s of batches of

Paracetamol tablet

failed in Dissolution

Page 54: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

6

Dissolution failure

100’s of batches of

Paracetamol tablet

failed in Dissolution

Page 55: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

7

Manufacturing with poor knowledge

Rivaroxaban Tablet

Failure in CDP

Page 56: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

7

Manufacturing with poor knowledge

Rivaroxaban Tablet

Failure in CDP

Page 57: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

7

Manufacturing with poor knowledge

Ramipril tablets

Process degradation

found

Page 58: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

7

Manufacturing with poor knowledge

Ramipril tablets

Process degradation

found

Page 59: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Able Laboratories, NJ

A story of Generic Manufacturing Company’s

Collapse

Page 60: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

1999 to 2005

Enormous growth & expansion

17 - 55% per share

Page 61: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

1999 to 2005

Enormous growth & expansion

17 - 55% per share

2005 - Major recall due to falsification of data

Flouting, altering or manipulation & reporting

Page 62: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

1999 to 2005

Enormous growth & expansion

17 - 55% per share

2005 - Major recall due to falsification of data

Flouting, altering or manipulation & reporting

2007 - Charged

All drugs withdrawn, company shut down

Page 63: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)
Page 64: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Lets hear and watch the way Leaders

come forward to protect trust

These are the norms of moral business

Page 65: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Closing Words

Audit communicate &

monitor your suppliers

Understand CQA of your product

Understand CPP of your process

Validate your process

Page 66: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Closing Words

Develop a Control Strategy

Maintain your

equipments & facility

Trend and monitor all

the components

Modify the Control

Strategy if required

Maintain the state of control

Page 67: Understanding of Product & Process for Installation of Appropriate Controls (12 April 2017)

Safe, efficacious

& have correct identity

Deliver the same

performance as claimed

Perform consistently over shelf

life

Made in a manner that

ensure quality

Will be available

when needed