OARO 11 Feb 2017

Discussion Forum

On

Assess, Challenge & Demonstrate Quality System

in your Manufacturing Facility

Obaid AliCivil Service Officer, Government of Pakistan

11 Feb 2017, Hotel PC, Karachi

Thanks for invitation

&

Opportunity to participate in discussion

Wish to have a Good Day of Knowledge Sharing

DISCLAIMER

Not the view of DRAP

Current judgment

No obligation on DRAP

Regulatory experience

Warm up exercise

Fundamental Scenarios of Manufacturing of

Healthcare Products

1

Thalidomide Tragedy

DiethyleneGlycol

Contamination

Heparin Catastrophe

Pyrimetamine MixupMedication

ErrorsCutter Incidence

Kellse

Quality Safety Efficacy Identity Purity Strength

0 50 100

Agree

Agree

0 50 100

Safety

Will you allow the use of a drug for yourself or your

loved one which is suspicious in terms of safety?

Safety

Can you catch presence of any toxic substance by testing

Efficacy

The drug is overheated in the dryer. What do you think?

Should it go to the market

Cleaning

An equipment is cleaned but not properly cleaned after

manufacturing of a male hormone. Time is not available

and you have to manufacture female hormone in the

same equipment.

What decision you think appropriate?

Consistency

Can you catch the variation in consistency

by product testing?

HVAC

Can you list what is harm, if we do not supply HVAC in

a manufacturing facility?

Documentation

Why do we rely on document only and do not rely on a

trustworthy person?

Validation

Instrument is not a human being. Why do we require

exercise to develop trust on equipment performance?

Process Parameters

…….. Dry at 15 to 20 minutes.

Why do not write dry up to 2% moisture level in batch

instructions?

Quality Attributes

What would be the harm if a tablet is cracked?

Why it is not acceptable?

Case Studies

Direct Questions & Discussion

2

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

Patient and

Doctor

assume that

Drugs are

Typically Consumer Can not

see Quality

Out of sight

Out of reach

May often look

like

Roohi B. Obaid, DDC, DRAP, Jan 2015

Plastic container

Bulk oral drug product

Washing in b/w use

No document to prove

It is cleaned

Residues removed

Its re-use

contamination

S, I, S, Q, P under question

Case study ….

Adequate assessment ?

Cross-contamination

risk

Manufacturing of several

hazardous compounds

High powder generation operation

Documented justification

lacking

Well designed contamination

prevention strategy lacking

Absence of sound design & control approach

w/o proper separation ….

Lacks assurance

That drug does not contaminate

another drug

Teva Pharmaceutical Industry, Israel

Inadequate cleaning procedure

Incomplete dis-assembly

Preventive maintenance not robust to detect potential

contamination

Study of placebo batches instead of

product for cleaning

Inadequate study

Cleaning procedure should be robust to ensure that no or

reasonable residue from previous batch remains

Apotex Incorporation Canada

Beta-lactam & cephalosporin

Personnel can freely move for collecting samples and

engaging in other activities

Failed to monitor surface sampling for

residual traces

Ranbaxy Laboratories Ltd, India

Tab Tramadolcontaminated with

Metoprolol HCl (19 Feb 2008)

Tablet Metoprololcontaminated with Metformin (25 Feb

2008)

The investigation was limited to

Tramadol tab after 2 months

Investigation was not extended to closely

related confirm incident

Other potential impact was not given

priority

Source of contamination was neither isolated nor

confirmed

Continued releasing of drug product at

the same time

……..

Story ended up with regulatory actions

Caraco Pharmaceutical Laboratories, USA

Material contaminated with tank (a waste tank of API, Intermediates & Solvents)

Aware in Jan 2012

Complete risk assessment in

April 2013

In b/w assessment you distributed

the batches

Some batches were rejected

Assessment approaches used were different

Ended up with warning letters

GSK, Cork, Ireland

GMP failures, Establishment of

contamination

A number of products were questionable

Matter expanded to criminal investigation

Story ended up in payment of $750 million for bad

products manufactured in a plant that was rife with contamination for years

GSK, Peurto Rico

Good Manufacturing Practices

Elements and their Role in Quality

3

Because

Drugs are public good and not simply just another commodity:

first for their high social value, and then because consumers and

prescribers are unable to assess their quality, safety and efficacy.

Quality cannot be observed by every one and/or by naked eye.

Quality cannot be tested in a laboratory but has to be built in to

the product

Trust on Safety, Efficacy & Quality

is not simple but so complex

What is cGMP & What it does?

Defined

Regulatory

Methodology to manufacture the

drugs

Protects

Integrity &

Quality of manufactured

product intended

for human use

Intent of GMP

• Identity, quality, and strength of pharmaceuticals.Provide assurance of

• Correct procedures are followed.Assure that

• Documentation, traceability.Provide

• Quality is “built in” to the approach.Overall Intent:

To assure

Pure

Consistent

Zero Mix Up

Drug Batches

1 2 3

Batch after Batch

Within Batch

Time after Time

GMP Elements

Premises Equipment Personnel Materials

DocumentationQualification &

ValidationEtc.

GMP Systems

Quality System

Production System

Lab Control System

Facilities & Equipment

System

Materials System

Packaging &

Labeling System

GMP System Indicators & Attributes

Complaints RecallInvestigations

& CAPAInternal Audits

Reviews

Change Management

Supplier Qualification

Risk Management

DeviationsMaster

Maintenance Plan

Master Validation

Plan

Master Training Plan

Calibration

Facility

Ventilation, Segregation of areas, Cleaning

Documents

COA & batch records, deviations

Equipment

Qualification

Product testing

Lack in finished product testing, Shelf-life data unavailable

Personnel

QC/production manager qualification independence of QC

Identify any

pattern of failure to

Control batches before release

Conduct investigation to resolve ….

Discrepancies, failure,

deviation, complaint

Aging Manufacturing Facilities & with Old Approaches

Lets unfold to understand

Uncertainty

Aging (Facility, Process, Analytics) and its Drivers

Due to lack of proactive Improvement Programs

Investment into appropriate Maintenance Plan

Area/

FlowEquipment AnalyticsProcess

Specific Risks of Older Factories

Inefficient Processes

Inappropriate material & personnel flows

Antiquated or obsolete ventilation system

Old equipment no longer meeting current requirements

Major change in facility! Does it worth?

Utilities HVAC (air changes etc), Water, Piping etc.

Systems Quality Policies & Compatibility

Premises Design, construction & maintainability

Flow Material, personnel, trafficking

Ways to keep align with modernization

Time wastage in quality documentation & administrative procedures?

Do you have adequate trained personnel in the maintenance unit?

Are adequate SOPs and maintenance protocols in place?

Analyze your number of defect rates, deviations?

Enhancing robustness

Improving production reliability

Adoption of new technologies leads to

Managing Values

Take Home Message

Keep an eye on ways

of Improvement

Always stay on the ball

regarding technology

Continuously adapt to

the changes

Implement improvement procedures,

perform risk assessment, analysis, set up

actions & document efforts

Keep abreast of new technologies &

processes. Work with your supplier to try to

improve your machinery on the shop floor

Try to implement a culture of quality and

improvement. The only constant thing is

change

Assessment of Manufacturing Facility

Maintain System & Making Change

Product & process

design with scientific

understanding is

critical

Knowledge Management

Product Development

Technology Transfer

Process Validation

Commercial Manufacturing

Basic Process Design (Process Validation)

CQA

Identification

Appropriate

Manufacturing Process

Suitable Control

Strategy

Impurity levels

Content Uniformity

Dissolution

Reactions

Equipment

Environmental

assessment

In process &

release testing

Proven Acceptable

Range/Normal

Operating Range

Process Qualification (Process Validation)

Building Design & Facilities

Understand &

incorporate

Material

Invariability

Process Performance

Qualification

Appropriateness &

Capability of Equipment

Fully evolved control

strategy for

commercialization

Protocol design, execution

& interpretation

Pre-Approval Inspection

ReadinessConformance to

ApplicationData Integrity

Equipment

Procedures

Quality

Management

Processes

Equipment scale

Process as

proposed

Submitted

information, raw

data & accuracy

Justification for commercial scale & process design not adequate

Commercial scale equipment not qualified, method not validated

Common Observations on Readiness (PAI)

Serious GMP deficiencies

Commercial scale equipment listed not available on-site

Implemented process does not match with the reported one

Common Observations on Conformance to Application (PAI)

Manufacturing process changes not reported

Averaging to hide fail results in data

Common Observations on Data Integrity (PAI)

Unknown

impurities

Retesting till

desired results

Not representative holding

studies

Use of trial

injectionsLack of audit trails

Failing results attributed to

analyst error

Continued Process Verification

Active proof that state of control is

maintained throughout the

process

Understanding of process & risk to develop a strategy

for monitoring

Variability potential in manufacturing & incoming material

properties assessment

Process Performance Qualification batches & reports

Stability & Shelf Life

Component Supplier Qualification

Post-Approval Inspection

Determination of cGMP Compliance & Quality Culture

Investigations to determine root causes & strengthen the quality

Deficiencies, Non-compliance & Violations

Surveillance Inspection

Discussion

on Events & Phenomena

4

Case Studies

1- Facilities & Equipment System

Repackaging of beta-lactams in a multiple packaging facility

Personnel move freely in common place from both ends

Story ended up with recall of the product

Manufacturing facility is ceased

Decontamination and renovation of facility

Publication of

warning letter

on public

domain

Safe level of penicillin ?

Can cleaning substitute?

Analytical method limitation?

Segregation alternatives?

Dedication waiver?

L

E

A

R

N

Case Studies

2- Packaging & Labeling System

Re-packaging of different drugs

Operator changes master labels

Change of master label without SOP

Complaints of low fill volumes

Recalled

Publication of

warning letter on

public domain on

inadequate

manufacturing

control

Repack may change characteristics

Change may impact safety & efficacy

Improper packaging, repackaging can cause ADR

Poor control may end up with disaster

Non-compliance with regulations

L

E

A

R

N

Case Studies

3- Production System

Pre-compressed blend samples … to determine operation parameters for tablet press

Use of different blends without any knowledge

Pre-compression practice observed during inspection

Inadequate release testing

Aware with the process problem

Publication of

warning letter on

public domain on

account of lack of

process validation

Operational parameters should be selected

using risk & science based approach

Process design must be completed and

adequate

Knowledge gained during scale up should be

incorporated in process design

Knowledge gained during scale up should

be incorporated in control strategy

Sampling plan for batch release should be

scientifically sound

L

E

A

R

N

Case Studies

4- Laboratory System

Multiple tarns dermal patches manufacturing for many years

Developed new drugs, utilized same adhesion matrix

5000 complaints received in 1st

year for efficacy and using difficulty

Up to 25% of drug was sticking to the liner

Drug adhesive interaction problem found

Caution

Firm argued, no specification for peel force

Did not recall and continued distribution

Ended up with recall

Peel force adhesion has to be established

Publication of

warning letter on

public domain on

account of lack of

specifications and

failure to assure

proper strength

L

E

A

R

N

Do not assume what worked before, will work

under different conditions

Don’t think, if it not happened, it will not

happen in future

Don’t think if inspection has been done, everything

will be good

Evaluate data to determine need for change

in specifications

Keep eyes open always

Case Studies

5- Materials System

Multiple adverse events and complaints that indicated presence of endotoxins in injectable drugs

Firm did not took serious and not identified a root cause

Regulatory inspection

Firm found in testing of endotoxinprior to terminal sterilization

Some tests were OOS but released on the basis of compliance of finished product

Keep thinking

Reason of high level of endotoxin in in-process testing?

Ceased materials and in-process testing

Recall

Thorough investigation

Eventually confirmed it came from raw material

Publication of

warning letter on

public domain

L

E

A

R

N

Testing is not the answer

Quality should be built in by design

Quality should be monitored

Quality should be controlled

Be vigilant, do needful, don’t assume and

leave unattended

Case Studies

6- Quality System

Contract giving to multiple sites

Contract services had several GMP problems

COA was the tool to review the materials

Found not reviewed versus specifications

Stability failures and complaints inadequately investigated

Publication of

warning letter on

public domain on

account of lack of

oversight by the

Quality Unit

L

E

A

R

N

Marketer (contract giver) is responsible

No matter who manufactured them

No matter who tested them

Don’t lose your reliability

Don’t put your name on thin ice

Lets demonstrate

Quality Management System

5

If something has not happened yet, it will likely not happen

Design may be flawed, but there is no evidence that there is a problem

If something has not been identified by inspector, it is ok

Passing the media fill assures process control

Lets correct, it is misconception

Sterility test has not yet failed but reason of pass is not defendable

We are complying and it is enough, no matter what you are referring

Traditional approach is a good approach

Insulin was filled in an area under exhaust fans in history

Lets correct, it is misconception

When calculated risk is the only option

Each and every caution is indispensible

GMP Elements

Premises Equipment Personnel Materials

DocumentationQualification &

ValidationEtc.

GMP Systems

Quality System

Production System

Lab Control System

Facilities & Equipment

System

Materials System

Packaging &

Labeling System

GMP System Indicators & Attributes

Complaints RecallInvestigations

& CAPAInternal Audits

Reviews

Change Management

Supplier Qualification

Risk Management

DeviationsMaster

Maintenance Plan

Master Validation

Plan

Master Training Plan

Calibration

Identify and Understand factors that impact product quality

Information is not knowledge

Let us not confuse the two

W. Edwards Deming

We are drowning in information

but starved for knowledge

John Naisbitt

Variations

Batch SizeMaster

FormulationManufacturing

SiteManufacturing

ProcessEtc.

Types of Contamination

Particulates

Micro-organisms

Cross-contamination

PA

RT

ICU

LA

TE

S

Dust

Dirt

Paper

Metal

Fiber

Etc.

MIC

RO

OR

GA

NIS

MS

Bacteria

Yeast

Moulds

CR

OS

S-

CO

NT

AM

INA

TIO

N Drug

Materials

Types of Cross-contamination

Source of contamination

Air

Water

Surface People

Pest

Weighing room…….

• Entry point …….to manufacturing

• Transit point …. For materials coming from warehouse and entering into the process area

Careful attention is indispensible

• Design…

• Layout….

• Operation

Principle derives the design of weighing room

(raw material staging, dispensing weighing, working process staging)

Unidirectional flow of

Materials

Personnel

Segregation between

Hazardous

Non-hazardous

Separation of

Storage … processed/intermediate

materials

Manufacturing items

Designated space

Remember Please …. To comply with GMP…establishment has to provide for every operation

Sufficient spacePhysical

separation

Adequate

• lighting

• Ventilation

• Utensils

• Equipment

• Facilities

Types of Human Error

Organizational/

systemic

Procedural (SOPs)

Careless work

Voluntary/

intentional

Involuntary

Material transfer

between unit process

with inadequate

assurance of integrity

and contamination risk

Dust extraction and

containment

Holding of process materials without study

Most common observations of US-FDA

No or inadequate procedures or not followed (production, cleaning, QC)

No management review of procedures

No Management oversight / QA oversight

No internal audits performed

Inadequate employee training

Inadequate validation (process mainly)

Inadequate laboratory controls

Incomplete laboratory notebooks

Lack of scientifically established specifications, sampling plans

Raw data not reviewed / maintained

Inappropriate investigation:

OOS, Recurring Deviations

Microbial contamination, Environmental monitoring excursions

Complaints, Temperature excursions during shipping

No procedures for corrective and preventive actions (CAPA)

Batch review inappropriate

Validation records

Second check not done for raw material additions & critical steps

Reprocessing not validated

Most common observations of US-FDA

10

Equipment Cleaning and Maintenance

7.1 %

7

Testing and Release

8.6.9 %

8

Personnel Qualifications/

Training

8.2 %

9

Batch Record Preparation/

Review

8.1 %

4

Laboratory Controls

9.9 %

5

Written Procedures

for Production

9.3 %

6

Investigations

9.1 %

Top 3

Most Common Observations

6

1

QCU Responsabilités

15.9 %

2

Adherence to Production Procedures

12.7 %

3

Production Procedures(Validation)

11.1 %

Regulatory world is

touching sky and getting so

complex

Requires interpretation and

somehow leniency to

promote evolution of science

such as off-label use by

physicians

Learn

De-learn

Re-learn

New

Tools

Approaches

Sta

nd

ards

E

Q

P

S

R

E

G

U

L

A

T

O

R

Y

S

C

I

E

N

C

E

Thanksoarohama@gmail.com