Upload
gv-narayana-reddy
View
224
Download
0
Embed Size (px)
Citation preview
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 1/47
Required GMP Standards
and Inspections
Alain Kupferman
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 2009
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 2/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 20092 |
Drug
meetingrequirements
Equipment Personnel
MethodsPremisesDefinition of conditions under
which drugs are manufactured,
packed, tested, held
State of Control:a drug firm is considered
to be operating in a state of
control when it can guarantee
a finished drug product
for which quality, strength and
purity has been assured
throughout production andthat the product is compliant
with its registration
STATE OF CONTROL
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 3/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 20093 |
ELEMENTS OF COMPLIANCE
EQUIPMENT COMPONENTS PERSONNEL FACILITIES PROCESS
QUALIFICATION ANALYSIS TRAINING QUALIFICATIONDEVELOPMENT
VALIDATION
PRODUCT
APPROVAL BY
AUTHORITIES
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 4/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 20094 |
S E L F -I N S P
E C T I ON
I N S P E C T I ON
MONITORING OF COMPLIANCE
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 5/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 20095 |
DEFINITIONS
Compliance
The state of conformity of a regulated party (including a corporation, institution,individual or other legal entity) or a product with a legislative or regulatoryrequirement.
Compliance Monitoring Actions planned to maintain regular surveillance in order to evaluate compliancewith applicable requirements of the National Regulatory Authority (NRA) and itsassociated Regulations.
This includes a wide variety of fact gathering and assessment activities such asinspections, market surveys and a product sampling program.
Compliance Verification Actions taken to verify compliance in response to information regarding known or suspected non-compliance with the applicable requirements of the NRA and itsassociated Regulations.This includes actions such as information gathering either off-site or via on-sitevisits.
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 6/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 20096 |
DEFINITIONS
Enforcement
Actions that may be taken to induce, encourage or compel compliance with the NRAand its associated Regulations.
Inspection
On-site monitoring and assessment against the applicable requirements of the NRA
and its associated Regulations.
Inspections are routinely conducted on a predetermined cycle or as required to assess
compliance.
Inspector
Any person designated as an inspector for the purpose of the enforcement of the NRA
Investigation
Actions taken to gather evidence to support a case referral for potential judicial
determination regarding specific violations of the NRA and its associated regulations.
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 7/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 20097 |
REASONS FOR INSPECTION
• Regular schedule based on general GMP’s
• Pre-approval inspections
• Submission of a variation
• Submission of an NDA
• New products and/or manufacturing changes• Site changes
• For cause inspections
• Recalls or significant complaint
• Past inspection history
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 8/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 20098 |
• Focus on Risk and Quality Systems
• Doctrine of Liability for Executives
• Process Analytical Technology
TRENDS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 9/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 20099 |
FOCUS ON QUALITY SYSTEMS & RISK
Quality Systems Inspection Program
Assess Firm's State of Control
Systems Approach (6 systems)
Executive ManagementExpected to Establish Effective Procedures and Controls toEnsure:
Timely Investigations
Supportable Decisions Are Documented
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 10/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200910 |
The idea underlying this approach is that
deficiencies in one systemwill affect all other systems as well.
FDA Systems Approach (6 systems)Quality System
Facilities System
Equipment System
Materials System
Production System
Packaging & Labeling System
FOCUS ON QUALITY SYSTEMS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 11/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200911 |
“Risk Based Pharmaceutical cGMP Initiative” Goals
(GMPs for 21st Century)the most up-to-date concepts of risk management and quality systems approaches
should be incorporated while continuing to ensure product quality (PAT);
the latest scientific advances in pharmaceutical manufacturing and technology
should be encouraged;
the submission review program and the inspection program should operate in acoordinated and synergistic manner;
regulation and manufacturing standards should be applied consistently;
management of the program encourages innovation in the pharmaceutical
manufacturing sector; and
FDA resources should be used most effectively and efficiently to address the most
significant health risks
FDA FOCUS ON QUALITY SYSTEMS & RISK
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 12/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200912 |
•Increased number of pharmaceutical products and a greater role of
medicines in health care
•Decreased frequency of FDA (NRA) manufacturing inspections as a result of
fewer resources available for pharmaceutical manufacturing inspections
• FDA’s (NRA’s) accumulation of experience with, and lessons learned from,
various approaches to the regulation of product quality
•Advances in the pharmaceutical sciences and manufacturing technologies
•Application of biotechnology in drug discovery and manufacturing
•Advances in the science and management of quality
•Globalization of the pharmaceutical industry
WHY A NEW FOCUS ?
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 13/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200913 |
RISK ASSESSMENT
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 14/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200914 |
RISK ASSESSMENT
RISK ASSESSMENT
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 15/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200915 |
RISK ASSESSMENT
RISK ASSESSMENT
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 16/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200916 |
RISK ASSESSMENT
RISK ASSESSMENT
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 17/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200917 |
RISK ASSESSMENT
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 18/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200918 |
RISK ASSESSMENT COMPONENTS
PRODUCT COMPONENT
PROCESS COMPONENT
FACILITY COMPONENT
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 19/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200919 |
1. Intrinsic factors
Factors such as sterility, medical gas, and the determination of prescription (Rx)versus over the counter (OTC) are crude methods to distinguish between products
with higher and lower potential for public health consequence should there be a drug
defect.
If there is a quality defect, sterile drugs would have a higher public health
consequence than nonsterile drugs; hence, sterile drugs should be given a higher
weight.Specific products where there is a heightened risk of cross-contamination, such as
sites manufacturing highly sensitizing agents (e.g., penicillin) and at least one other
product using similar processing methods should be taken into account.
2. Past recalls for quality defects / Complaints
Drug recall data provide information on past recalls for quality defects with potentialfor human health hazard.
PRODUCT COMPONENT
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 20/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200920 |
Some processes are more complex and more susceptible to problems than
others.
A primary goal of CGMP inspections is to ensure that processing operations
are in a state of control.
Two types of process-related factors were identified for inclusion in the risk-
ranking model:
1. Factors associated with maintaining process control
2. Factors associated with potential vulnerability to product or
environmental contamination
PROCESS COMPONENT
PROCESS COMPONENT
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 21/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200921 |
It is important to arrive to a risk-ranking (i.e., from high to low) of the
probability of a loss of a state of control and, independently, the
vulnerability of the process to contamination for a product category and
processing operations associated with that product category.
It is necessary to survey on risks associated with commonly employed
manufacturing operations (e.g., measuring, mixing, compression, and
filling) and for a variety of product categories (e.g., immediate and
modified release solid-oral drugs, sterile liquids, metered dose inhalers,
and active ingredients by chemical and fermentation processes).
PROCESS COMPONENT
PROCESS COMPONENT RISK MANAGEMENT
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 22/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200922 |
PROCESS COMPONENT: RISK MANAGEMENT
ICH Q9
FACILITY COMPONENT
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 23/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200923 |
The facility component of the US FDA risk ranking model includes 4factors:
1. History of violation (e.g., CGMP deficiencies have higher weights)
2. History of inspection (e.g., no prior inspection, newly registered/
licensed or no CGMP inspection in the past 2 years have higher
weights than those with recent CGMP inspection)
3. Estimated volume of production output (surrogate for exposure,
e.g., higher volume and production output, higher weights)
4. Type of establishment (e.g., manufacturer, repacker, contract lab)
FACILITY COMPONENT
MANAGEMENT CONTROLS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 24/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200924 |
MANAGEMENT CONTROLS
Strict Liability Requires Diligence & Management Controls to:
• Prevent Violations• Detect Problems When They Occur
• Correct Root Cause Issues
Indiv iduals Corporations Act Through
Can Be Held AccountableIndiv iduals
The FD&C Act
“…dispenses with the conventional requirement for criminal conduct -- awarenessof some wrongdoing.“
“…a positive duty to seek out and remedy violations when they occur … and …, a
duty to implement measures that wil ensure that violations will not occur.”“…and permits conviction of responsible corporate officials, who … have thepower to prevent or correct violations”
PROCESS ANALYTICAL TECHNOLOGY
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 25/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200925 |
PAT is considered to be a system for
•designing ,
•analyzing, and
•controlling manufacturingthrough timely measurements (i.e. during processing)
of critical quality and performance attributes of raw and in-
process materials and processes with the goal of ensuring final
product quality.”
PROCESS ANALYTICAL TECHNOLOGYPAT
PROCESS ANALYTICAL TECHNOLOGY
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 26/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200926 |
1. PAT Tools
2. Process Understanding
3. Risk-Based Approach
4. Integrated Systems Approach
5. Real Time Release
PROCESS ANALYTICAL TECHNOLOGY
PROCESS ANALYTICAL TECHNOLOGY
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 27/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200927 |
1. PAT Tools
•Multivariate data acquisition and analysis tools
•Modern process analyzers or process analytical chemistry tools
•Process and endpoint monitoring and control tools
•Continuous improvement and knowledge management tools
2. Process Understanding
A process is generally considered well understood when
•all critical sources of variability are identified and explained;
•variability is managed by the process; and,
•product quality attributes can be accurately and reliably predicted over the ranges
of acceptance criteria established for materials used, process parameters, and
manufacturing environmental and other conditions.
The ability to predict reflects a high degree of process understanding.
Although retrospective process capability data are indicative of a state of control,these alone may be insufficient to gauge or communicate process understanding
PROCESS ANALYTICAL TECHNOLOGY
PROCESS ANALYTICAL TECHNOLOGY
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 28/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200928 |
3. Risk-Based Approach
Within an established quality system and for a particular manufacturing process,
there is an inverse relationship between the level of process understanding and
the risk of producing a poor quality product
4. Integrated Systems Approach
Development, manufacturing, quality assurance, and information/knowledge
management functions
5. Real Time Release
Real time release is the ability to evaluate and ensure the acceptable quality of
in-process and/or final product based on process analytical data
PROCESS ANALYTICAL TECHNOLOGY
PROCESS ANALYTICAL TECHNOLOGY d ICH
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 29/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200929 |
PROCESS ANALYTICAL TECHNOLOGY and ICH
PROCESS ANALYTICAL TECHNOLOGY d ICH
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 30/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200930 |
PROCESS ANALYTICAL TECHNOLOGY and ICH
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 31/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200931 |
Error Precursors
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 32/47
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 33/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200933 |
FINDINGS FROM INSPECTIONS
Source:MHRA (MCA)
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 34/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200934 |
FINDINGS FROM INSPECTIONS
Source:MHRA (MCA)
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 35/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200935 |
FINDINGS FROM INSPECTIONS
FINDINGS FROM FDA INSPECTIONS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 36/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200936 |
FINDINGS FROM FDA INSPECTIONS
FINDINGS FROM FDA INSPECTIONS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 37/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200937 |
FINDINGS FROM FDA INSPECTIONS
FINDINGS FROM FDA INSPECTIONS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 38/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200938 |
FINDINGS FROM FDA INSPECTIONS
INSPECTION RESULTS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 39/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200939 |
Buildings and Facilities
•Not of adequate size or capacity for intended activities
•Failure to provide separate or defined areas to prevent contamination, cross-contamination or
mix-ups
•No appropriately cleaned or maintained
•Effectiveness of sanitation has not been established
•Poorly designed air handling systems or not appropriate for intended activities
•Not monitored for temperature or humidity
•Poorly designed water systems
•Poor hygienic zone system
•Use of low quality building fabrics leading to easily damaged walls and doors which become
difficult to clean
• Incorrect airflows and pressure differentials to prevent cross contamination
• Sterile area changing rooms insufficient in size or bqd lqyout
• Goods receipt areas of insufficient size
INSPECTION RESULTS
INSPECTION RESULTS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 40/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200940 |
Equipment
• No or improperly maintained cleaning and usage logs
•No expiration dating of cleaned equipment
•No or inadequate cleaning validation
•Not identified as to use or status•No or insufficient SOP for use
•Not or incorrectly identified in batch record
•Inadequate calibration program
•Preventative maintenance program not in existence or inadequate
INSPECTION RESULTS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 41/47
INSPECTION RESULTS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 42/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200942 |
Quality Management Systems, Records and Reports
•Incomplete batch and test records:
- Steps not verified
- Laboratory results not included
- Equipment not identified
•Not reviewed or revised periodically
•Inadequate documentation of deviations and OOS •Incomplete or tardy recording and investigation of complaints and incidents
• No regular management review of quality indicators
• Lack of quality improvement / CAPA processes
• Insufficient change control
• Ineffective self -inspection systems
• Recall systems incomplete and untested
• Non-compliance with previous inspection commitments• Inadequate recording of training and effectiveness
•Insufficient documentation of maintenance and calibration activities
INSPECTION RESULTS
INSPECTION RESULTS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 43/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200943 |
Laboratory Controls
•Not based on scientifically sound and appropriate
(specific) specifications
•Test methods not appropriately validated
Standard Operating Procedures (SOP)
• Not in existence.
•Incomplete or not in sufficient detail
•Not followed or deviations not justified
•Not periodically reviewed and updated
INSPECTION RESULTS
INSPECTION RESULTS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 44/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200944 |
Procedures and Process Controls
• Aseptic processing principles not applied or validated:
- Not all aseptic processes are included in challenge studies.
- Product exposed to environment that is not properly controlled.
- Failure to validate aseptic connection.
- Failure to follow SOP.•Investigations following excursions not performed, documented or
are inadequate:
- Do not include other batches associated with failure.
- Are not completed in timely manner.
INSPECTION RESULTS
INSPECTION RESULTS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 45/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200945 |
Procedures and Process Controls
• In-process hold times not validated or incorporated into stability program
•Sterilization procedures not appropriately validated or revalidated•No or inadequate process validation studies or in-process testing
•Inadequate changeover procedures for multi-purpose areas
•No time limits for completion of time-sensitive production phases
INSPECTION RESULTS
INSPECTION RESULTS
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 46/47
Workshop on WHO prequalification requirements for reproductive health medicines,
Jakarta, October 200946 |
Environmental Monitoring
• Not performed during manufacturing operations
•Appropriate limits:
- Not based on trends
- Do not consider nature of the product
•Inadequate monitoring frequencies
•Improper location of sampling devices or monitoring locations not identified
No viable monitoring close to point of fill for aseptic products
Poor handling and positioning of settle plates in critical zonesPoor or no continuous particle monitoring in critical zones
•Inadequate personnel monitoring
•Wash bays, cold stores and water systems not monitored microbiologically
• No monitoring during or following building work
• No assessment of recovery or growth promotion
•Sampling procedures not representative of usage procedures
•Data not linked to manufacturing process •Investigation following excursions are no performed,not documented, or inadequate:
- Are not complete, do not consider impact on product, are not completed in timely manner
•Procedures allow for consecutive out of specification results before taking action
INSPECTION RESULTS
CONCLUSION
7/27/2019 4-2 Inspections GMP Standards
http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 47/47
Workshop on WHO prequalification requirements for reproductive health medicines,|
CONCLUSION
Adopt the mindset
Be prepared and compliant all the time,
NOT just at the time of the inspection
Conduct at regular intervals
Inspection Readiness Training
Self Audits
Integrate audit program with overall system based GMP program.