Transcript Vipul Doshi - compliance road map

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 company’s 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, it’s required
Round the Clock
Warning Letters Issued
•Total 26 warning letters issued in the year 2011
Warning letter
12
10
10
8
8
6
Yr 2011
4
4
2
2
1
1
0
API
API (Sterile)
QC
Solid
Gel
Injectables
Regulators Speak through
Regulations
GLP
GAMP
Good Laboratory Practices
21 CFR Part 58
40 CFR Part 160 ( EPA )
Good Automated
Manufacturing Practices
GAMP 5(ISPE) Guide
cGMP
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
GALP
Good Automated Laboratory Practices
EPA Directive 2185 ( 1995 Ed. )
ICH Guidelines
Quality, Efficacy, Safety, CTD / e – CTD
GCP
Good Clinical Practices
21 CFR 312 Sub part
Q1A(R2)
Q1B
Q1C
Q1D
Q1E
Q7
Q8(R1)
Q9
Q10
M4(R3)*
Stability Testing
Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
Pharmaceutical Development
Quality Risk Management
Pharmaceutical Quality System
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 inprocess 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.
Guidelines Revised / Issued
16
14
12
10
8
6
4
2
0
14
10
9
2
1
1
1
1
2
2
2
1
Indian Pharmaceutical
Industry Overview
Challenges
FDA Today
FDA Today
FDA Today
Pillars of Compliance
Compliance
Man
Materials
Equipments
Environment
Facility & Infrastructure
Operations
R&D
QA
QC
RA
Compliance Approach
Quality Assurance Systems
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 it’s
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 manufacturer’s 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
 Supplier’s labels
What’s Involved
 Starting Products
 Specification
 Certification
Raw Materials Manufactured Products
Active Ingredients Excipients
Measurable ,Attainable ,Simple
Proper Storage Types of Testing
Qualitative Quantitative
Process Variation and ControlSeven (7) M’s
Management
Materials
Man
Methods
Input
Process
Output
Measurement
Medium
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
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
(To specify the
end use requirement)
Design
(By manufacturer to
meet expectations)
Manufacturing of
Equipment
(Easy to handle,
Easy to clean.
Good surface
Finishing)
FAT
(To ensure for
functioning as per
expectation at
manufacturing site)
Retirement
Usage Evaluation
SAT
(Receive at site
In proper condition)
BM
Breakdown
Maintenance
(Trending)
PM
(Preventive Maintenance
to maintain equipment
as per functionality)
PQ
Placebo run
(Matrix approach to
qualify for
intended use)
IQ/OQ
Qualify equipment
as per SOP
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
Validate Status
Document
Evaluation & Risk
Assessment
Validation
Report
System
Specification
Validation
Documentation
Update
System Test
Procedures
System
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
Challenge
3 Process
Validation:
General
Principles and
Practices WEF:
Jan'11
Action
Stage 1- Process design: (The
commercial manufacturing process
is defined during this stage based
on knowledge gained through
development and scale-up
activities).
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).
Impact
Robust manufacturing
process.
Compliance to the
regulatory requirement.
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
Quality by Statistical Process Control
Review of historical output of process to
identify the limits of a stable process and
source of error.
Quality by Inspection
Inspect
Approve / Reject
Pharmaceutical Quality System
Change
Control
Planned
Modification
Out Of Trend
Training
Internal
Quality Audit
Event
Investigation
CAPA
Market
Complaint
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
Identify &
Triage
Investigate,
Root
Cause,
Action Plan
 Identify problem  Complete
Investigation
 Assess impact
 Quality /
Regulatory /
Management
Notification
 Investigation
Process?
Change Control
Review &
Approve
Plan
 Assess
changes
 Determine Root  Ensure no
Cause
impact to
product quality
 Proposed
Corrective /
 Consensus
Preventive
from reviewers
Actions
 Approval
 Plan
effectiveness
Impleme
nt
Actions
 Implement
Actions
 Verify
Completeness
 Inform
stakeholders
Verify
Effectiveness
 Measure to
ensure
problem has
been resolved
 Monitor to
ensure it is not
re-occurring
CAPA Sources
Supplier
Audits
Regulatory
Audits
Adverse
Trends
Nonconformance
Complaints
Adverse
Events
Deviations
Out of
Specification
Internal
Inspections
Incoming
Inspections
Out of
Specification
And more…
• 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)
Culture on Risk
Communication
Training
Of
Personnel
Implementation of
Risk Control
Measures
Risk
Graph
Residual
Risk
Risk
Hazard
Cause
Verify
Effectiveness
Post
Production
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!