Compliance Road Maps

Vipul Doshi

Sun Pharmaceutical Industries Limited

 Preamble
The Pharmaceutical Industry is constantly being challenged to comply
with rigorous regulatory requirements.

Satisfying regulatory agencies that a companys processes are being

operated at a level of control that will ensure that their products will meet
predetermined safety, efficacy and quality specifications.

Compliance is evolving from an isolated departmental initiative to an

enterprise level risk management challenge.

However, compliance is not a one-time event and organizations are

redesigning their compliance programs to make them repeatable
processes that could be sustained.
 Cost of Non Compliance
Regulators Act !
Non Compliance Observations
Warning Letter (WL)
Import Alerts
Withheld Approvals
Cancellation Of Government
Contracts
Product Recalls
Seizures
A Consent Decree Of
Permanent Injunction
Civil Money Penalties
Suspension / Revocation
Prosecution
Who Governs
 Challenges

Rising Standards of Quality

Rising Regulatory requirements and reporting
mandates
International Regulatory Requirement Harmonization

Compliance is not one

time requirement, its
required Round the Clock
Warning Letters Issued
Total 26 warning letters issued in the year 2011
 Regulators Speak through
Regulations
GLP GAMP
Good Laboratory Practices Good Automated
21 CFR Part 58
40 CFR Part 160 ( EPA ) cGMP Manufacturing Practices
GAMP 5(ISPE) Guide
Current Good
Manufacturing Practices
21 CFR Part 211 ( Pharma )
21 CFR Part 820 ( Med devices)
21 CFR Part 110 ( Food )
21 CFR 600 680 Biologics
GCP
GALP Good Clinical Practices
21 CFR 312 Sub part
Good Automated Laboratory Practices
EPA Directive 2185 ( 1995 Ed. )
Q1A(R2)
Q1B
Q1C Stability Testing
Q1D
Q1E
ICH Guidelines Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
Quality, Efficacy, Safety, CTD / e CTD Q8(R1) Pharmaceutical Development
Q9 Quality Risk Management
Q10 Pharmaceutical Quality System
M4(R3)* Organization of the Common Technical Document for the Registration of
Pharmaceuticals for Human Use
Regulators Speak through
Regulations
GMP guidelines comprise strong recommendation on
Quality Management, Personnel Production, Facility and
Equipment, Documentation and Records, Product and in-
process Control, Packaging and Identification, Labeling,
Storage and Distribution, Laboratory Controls, Validation,
Complaint and Recalls, and Contract Manufacturers.

The WHO version of GMPs was prepared in 2004 (20th

World Assembly) from then, there are several amendments
and extensions of the guidelines.

Schedule
M (1987): Good Manufacturing Practices and
requirements of Premises ,Plant and Equipment for
Pharmaceutical Products were regulated.

Schedule M (2001) : Stringent norms to match with

Global requirements were devised.
Regulatory Guideline Updates
In the year 2011, total 46 changes in the guidelines were published.
 Indian Pharmaceutical
Industry Overview

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FDA Today
FDA Today
FDA Today
 Pillars of Compliance

Compliance
Compliance
Man

Materials

Equipments

Environment

Facility & Infrastructure

Operations R&D QA QC RA
Compliance Approach
 p ly
o m
I C
D o Quality Assurance Systems
w
Ho Analytical Control

Validation & Calibration

Equipment Control

Process Control

Material Control

Supplier Management
 Supplier Management

Importance of Knowing the supply chain

Using a pharmaceutical ingredient without

knowing the manufacturing location, where its
been, and how it got to you is like using a
toothbrush found lying in a public restroom.
 Supplier Management

Gold Sheet May 2012

FDA inspections last year identified more

problems in the global supply chain, of the 52
warning letters issued in FY 2011,17 went to
active pharmaceutical Ingredient manufacturers
up from 8 in FY 2010
 Excerpts of Non-Compliance

Your vendor qualification has not provided adequate evidence that the
manufacturer can consistently supply raw materials that meet appropriate quality
attributes

You did not specify how you intend to document and implement such audits

Your firm accepts suppliers certificates of analysis (COA) without having

qualified the vendor

Your firm has not conducted at least one specific identity test and has not
established the reliability of the supplier's analyses through appropriate
validation of the supplier's test results at appropriate intervals"

In addition, you failed to appropriately validate your suppliers' test results (as
furnished to you on the suppliers certificates of analysis) at appropriate intervals
 Challenges in Assuring Supply Chain
Quality System Vulnerabilities
Often vendor audits restricted to the evaluation questionnaire and
obtaining TSE/BSE certifications

Certificates of analysis (COAs)

Over reliance on COAs
Original manufacturers COA not always obtained
COA often altered to remove true identity of manufacturer
Reported test results may be unreliable or falsified

Supplier qualification programs, quality agreements, and lifecycle

monitoring are often deficient

Distant manufacturing sites

 Pharmaceutical Ingredient Supply
Chain A Shared Responsibility!
Manufacturers & Distributors
Are responsible for assuring that ingredients they supply comply GMP, are not
misbranded or contaminated, are packaged/stored appropriately, and adhere to
contract

End Users
Are ultimately responsible for the use of appropriate ingredients and
assuring ingredient quality at every stage of the supply chain
 Incoming Material Control
Purchasing important operation

From approved suppliers if possible, direct from the

manufacturer

Specifications for materials

Consignment checks
Integrity of package
Seal intact
Corresponds with the purchase order
Delivery note
Suppliers labels
 Whats Involved

Raw Materials Manufactured Products

Starting Products
Active Ingredients Excipients

Measurable ,Attainable ,Simple

Specification

Proper Storage Types of Testing

Qualitative Quantitative
Certification
 Process Variation and Control-
Seven (7) Ms
Management

Materials
Man Methods

Input Process Output

Medium Measurement
Machine

Process Analytical Technology PAT THE NEW INITIATIVE

Real time automatic testing and control
Continuous real time assurance of Quality through feedback control system
 Process Control
Process control by Trending
Trending of applicable data and its analysis to determine
the performance of the product quality ,over a period of
time and provides an opportunity to take appropriate
decisions. The methodology and techniques of
computation of data, preparation of control charts and
knowing the process capability are simple tools which
can be used successfully to identify potential problem
areas to facilitate corrective and preventive measures
which will go a long way in improving product
consistency,quality,its performance in the market within
compliance framework as per regulatory agencies.
 Process Control

Selecting process to improve Measuring improvements in process capability

n t p
ify m on e
ew -u
t e le se i em i w
en if n ob
u ut l v llo
Id De r Ca So
l p Re Fo
P Im

Measuring ability of process to meet its specification limits

Root Cause Analysis

 Equipment Controls

Equipment must be located, designed, constructed,

adapted and maintained to suit the operations to be
carried out.

The layout and design of equipment must aim to

minimize the risk of errors.

Permit effective cleaning and maintenance in order to

avoid cross-contamination, build-up of dust or dirt,
and, in general, any adverse effect on the quality of
products.
 Equipment Controls Life Cycle
URS Design
(To specify the (By manufacturer to Manufacturing of
end use requirement) meet expectations) Equipment
(Easy to handle,
Easy to clean.
Good surface
Finishing)

FAT
(To ensure for
functioning as per
Retirement expectation at
manufacturing site)

Usage Evaluation
SAT
(Receive at site
BM
In proper condition)
Breakdown
Maintenance
(Trending)
PQ IQ/OQ
PM Placebo run Qualify equipment
(Preventive Maintenance (Matrix approach to as per SOP
to maintain equipment qualify for
as per functionality) intended use)
 Calibration
What ?
A set of operations that establish, under specified conditions, the relationship between the
values of quantities indicated by a measuring instrument or measuring system, or values
represented by a material measure or a reference material, and the corresponding values
realized by its standards.

Why ?
When process measuring instruments age and experience physical stress or temperature
variations, critical performance gradually declines. This is called drift.

The slow variation with time of metro logical characteristics of the measuring instruments.
As a result of this, the measurement results become unreliable and ultimately the production
quality can suffer.

Drift cannot be eliminated, but it can be discovered through calibration.

 Calibration
BENEFITS

Calibrated equipment provides confidence that products/services meet their

specifications.

Calibration:
Increases production yields,
Optimizes resources,
Assures consistency and
Ensures measurements (and perhaps products) are compatible with those made
elsewhere.
By making sure that measurements are based on international standards, promote
customer acceptance of the products around the world.

Neglecting calibration can lead to unscheduled production downtime, quality

problems and product recalls.

Risking employee safety.

Risking customer/consumer safety. Loosing license to operate due to not meeting

regulatory requirements.
 Validation
General Validation Comments

Results MUST be repeatable

Validation must be standardized

Validation must meet industry standards

Validation Legacy System Life Cycle
System
Retirement

Validation Plan
Maintaining
Con Validate Status
fi rms
Document
Evaluation & Risk
Assessment Res Validation
p ond Report
s

System
Specification Veri Validation
fies Documentation
Update

System Test System

Procedures Qualification
 Validation - Challenges
Risk-based approach.
Conduct appropriate levels of GxP impact and criticality risk assessment of
systems and system functionality early in the planning stage and then
throughout the validation life cycle as required.

Computer System Validation

Map the stages and terminology of Information systems, e.g., enterprise
resource planning (ERP) and Laboratory Information Management Systems
(LIMS) with the recognized validation life cycle model.

Cleaning Validation
Appropriate and sensitive method to determine low level to meet MACO
 New FDA guidance on Process
Validation January 2011
Challen Action Impact
ge
3 Process Stage 1- Process design: (The Robust manufacturing
Validation: commercial manufacturing process process.
General is defined during this stage based
Principles and on knowledge gained through
Practices WEF: development and scale-up Compliance to the
Jan'11 activities). regulatory requirement.
Stage 2 Process Qualification:
(During this stage, the process
design is evaluated to determine if
the process is capable of
reproducible commercial
manufacturing).
Stage 3 Continued Process
Verification: (Ongoing assurance is
gained during routine production that
the process remains in a state of
control).
 Analytical
Good Quality Control Practices-
- Personnel, Premises and Equipment in Laboratories should be

appropriate as per the tasks.

- Laboratory Controls Documentation ,Sampling ,Testing
A management system to assure the quality and integrity
of data underlying a study

All records to be retained

 Analytical

Effective specification and method

Appropriate instruments
Effective calibration program
Effective preventive maintenance program
Qualified personnel
Effective standard management
Effective and usable SOP for OOS and OOT
Trending of laboratory failure and CAPA
Effective sample management

Glassware
Controls
 Analytical
Current Issues
OOS

Investigation is too brief and templated before Retesting begins.

Checklist of possible causes not used, used incorrectly or incompletely.

Equipment not Qualified or not within Calibration window. PM not performed per
SOP or recently.

Standard (solid, stock solution and dilution expired).

Spreadsheet Application for calculation(s) not Qualified and incorrect.
Method version changed and not accessible to analyst or analyst has not
checked (going from memory)
Wrong or expired Reagents, Solvents, Titrants, etc., used.
 Analytical
Current Issues
Wrong or damaged volumetric glassware used.
System results have changed significantly (I.e., System Suitability
parameters).
Analytical method not followed correctly.
Results yield much higher variability than found in original method
validation.
Sample preparation error made (e.g., weighing, sampling, dilutions).
Environmental room conditions changed (e.g., room temperature or light
excursion).
Reagent or solvent contamination present.
Sample identification transcribed incorrectly.
 Pharmaceutical Quality System

ach
ro
p p
e A
ti v i ve
a c Pro
ac t

Pro
t o
ive
a ct
Re
e
it v Quality by Statistical Process Control
ac Review of historical output of process to
Re identify the limits of a stable process and
source of error.

Quality by Inspection
Inspect Approve / Reject
Pharmaceutical Quality System
Effective Tools for Compliance

Current Expectation of Regulators

CAPA is much more than just corrective actions

and
preventive actions.
Any opportunity to improve quality in the organization is a CAPA!

Risk Management : Systematic application of management policies,

procedures, and practices towards analyzing, evaluating, and
controlling risk.
 CAPA Process Best practices
Regardless of where the problem originates, or what type it is, it
must follow a process

Metrics and Reporting Change Control

Investigate,
Review & Implement Verify
Identify & Triage Root Cause,
Approve Plan Actions Effectiveness
Action Plan

Identify problem Complete Assess Implement Measure to

Investigation changes Actions ensure
Assess impact
Determine Root Ensure no Verify problem has
Quality / been resolved
Cause impact to Completeness
Regulatory /
Management Proposed product quality Inform Monitor to
Notification Corrective / stakeholders ensure it is not
Consensus
Preventive re-occurring
Investigation from reviewers
Process? Actions
Approval
Plan
effectiveness
 CAPA Sources
Supplier Non- Out of
Deviations
Audits conformance Specification

Regulatory Internal Out of

Complaints
Audits Inspections Specification

Adverse Adverse Incoming

And more
Trends Events Inspections

Numerous source areas for CAPA

Scope of problems that drive CAPAs go beyond
nonconforming product
Any process that affects product quality is included
ICH Q9 Quality Risk
Management
 Corporate Risk Management
Program
RM
Policy

An Integrated Risk
Management Process
(for all phases of the life of the product)

Risk
Culture on Risk
Risk Hazard
Communication
Graph Cause

ImplementationResidual
of
Training Verify Post
Of
Risk ControlRisk Production
Effectiveness
Personnel Measures Monitoring
Road to Compliance
Road to Compliance
When it comes to ensuring drug product quality and ultimately
Consumer/Patient Safety . . . We need to think and act globally!