IF IT WAS NOT DOCUMENTED, THEN IT WAS NOT DONE”
Fundamentals of US Regulatory Affairs
Chapter 8
Objectives
• Understanding GMP
• Understanding basic quality system concepts
and quality system regulations
• Overview of key GMP regulations
• Differences and similarities between
pharmaceuticals and medical devices
• Concept of clean design and process
validation
Objectives (cont)
• Basic elements of sanitary equipment design
• Effective cleaning and sanitation programs
• CAPA system (Corrective And Preventative
Action)
• Cross-contamination risk within the
manufacturing environment
cGMP
(Current Good Manufacturing Practice)
• GMP should be “Designed” to be flexible to allow each
manufacturer to decide individually how to implement
the necessary controls by using scientific sound design,
processing methods and testing procedures
• The “C” in GMP means current – up to date
technologies
• Overall concept
– Quality should be built into the product
– Testing alone cannot be relied on to ensure product quality
• A product that is ‘fit for its purpose”
cGMP Principles
• Build QUALITY in - you cannot test or inspect
quality in to a product – it must first be quality
• Have controls in place for each step of the
process – increase the likelihood the product
produced in safe and fit for its intended
purpose
• Product the product from contamination and
cross-contamination and prevent mix-ups.
cGMP Principles (cont)
• Know what you are doing in advance and
document what really happened (document
everything)
• Work towards consistency and control and
monitor your system
• Have an independent Quality Assurance
Group
GMP is global
• It is influenced by international bodies
– ICH
– International Organization for Standardization
(ISO)
– cGMP Harmonization Analysis working group (FDA
2003) Modify 21CFR210 and 211 to meet ICH
GMP Regulations
• Non-biologics – FD&C Act section 501(a)(2)(b)
• Finished Pharmaceuticals – 21CFR211 – Clinical supply
dosage forms (including placebo) and commercially marketed dosage form
• ICH Q7A GMP for Active Pharmaceutical Ingredients
• Biologic Drug Products – 21CFR 210 and 211; 21CFR 600-680;
comply with BLA commitments and applicable standards
• Quality Systems - ISO9000, non-US Pharmaceutical
quality management requirements FDA Quality
Requirement System (QRS)
• Guidances and CPGM (Compliance Program Guidance Manuals) –
for FDA GMP inspections – details cleaning validation, water systems,
microbiological and QC labs, sterile bulk substance
cGMP Requirements
(as many regulations as GCP)
• A Quality System (change control, validation,
CAPA
• Qualified and trained personnel
• Fit for use buildings and facilities to meet the
purpose
• Equipment that is suitable, clean, maintained
and calibrated
cGMP Requirements (cont)
• Controls in place to prevent degradation or
contamination of materials (raw, in process
and final)
• Production and in-process controls for
performance monitoring and deviations
• Proper packaging and labeling – ID and
Protection
• Laboratory controls – specifications , samples,
testing
Generic Drugs and GMP
• Is identical or bioequivalent to a brand-name
drug in dosage form, safety, strength, route of
administration, quality, performance
characteristics and intended use
• Analytical testing of the chemical composition
of the generic is determined to be the same as
the branded product
Medical Devices
• FD&C Section 501(h) and 520(f)(1)
– Amended in 1976 - Medical Device Amendment
– 1978- Device GMP initiated
– 1996 – Revised ‘Quality System Regulations’
• Human factors techniques and data should be integral
considerations in all medical device design control
components
• Each manufacturer must establish and maintain procedures
for verifying the design input
• Design validation must ensure devices conform to defined
user needs and intended users and must include testing of
production units under actual or simulated use conditions
• Design validation must include risk analysis and use error
Combination Products
• Utilize the capabilities of two or more
different product types to provide effective
health care (21CFR3.2(c)) and cGMP (21CFR
Part4 Subpart A)
• The drugs and devices are still covered by
individual regulations (21CFR210 and 211;
21CFR810 respectively)
cGMP for Phase 1 Investigational Drugs
• Guidance for Industry: Current GMP Practice for
Phase 1 Investigational Drugs (July 2008)
• 21CFR201.2 – If the Phase 1 drug is already
marketed or used in Phase 2 or 3 trials, then it is
exempt from 21CFR211
• Trial Materials need
– Well-defined and written procedures
– Adequately controlled equipment and manufacturing
environment
– Accurately and consistently recorded data
cGMP for Phase 2 and Phase 3 Investigational Drugs
• Guidance: Preparation of Investigational New
Drug Products (1991)
Adulterated Drugs or Devices
• A drug or device is considered adulterated unless
it is manufactured in conformity with cGMP
practices (newest industry standards)
• A robust quality system is required to provide the
necessary framework for implementing Quality
by Design, continuous improvement and risk
management
• Whether documented on paper or electronic all
data must be able to be traced back to the source
and verified
Device Quality System Regulation (QSR)
• Quality System is the organizational structure,
responsibilities, procedures, processes and
resources for implementing process management
– Medical devices QSR are found in 21CFR820
– ICH Pharmaceutical Quality System Q10
• QSR states specific requiremnts for such key
elements as management responsibility, quality
planning, CAPA, design controls and purchasing
control
Corrective And Preventive Action
(CAPA)
• Each Device manufacturer must maintain history
files, a device ,aster record and a device history
record for each type of device
• Every company must have quality plans and
quality system records that define its quality
practices
• Device Manufactures are required to establish
purchasing controls and institute postdistribution device failure investigations and
CAPA for defects or recurring technical problems
Pharmaceutical Quality System
• Guidance for Industry: Quality Systems Approach to Pharmaceutical
cGMP Regulations (June 2006); 21CFR210 and 211
• The six-system inspection model
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Quality system
Facilities and equipment system
Materials system
Production system
Packaging and labeling system
Laboratory controls
• Robust Quality System will have
– SPOs
– Training
– Records and good documentation practive
QC vs. QA
Quality Control vs. Quality Assurance
• The QC unit monitors overall compliance with
cGMPs
• The QA units supplies oversight by auditing
the functions
• They identify and investigate OOS (Out-ofSpecification) results, deviations and failures
in both production and the analytical
laboratory.
Facilities and Equipment System
• Areas are designated as clean and dirty,
– Physical separation, equipment and staff for each
operation
• Specify personnel protection equipment and to
prevent contamination by humans
• Areas must operate to a single standard - GMP or
non-GMP
• Need to have designed into areas
– Building materials, air handling, temperature,
microbiology
Records
• Distribution records must be maintained to
aid in recalls
• Environmental Controls, Support systems,
Alerts, Action Limits must be established
• The environment must be controlled and
monitored to prevent product crosscontamination and contamination by harmful
microorganisms or extraneous matter (filth)
Microbiology
• Effects on product
– Causing human illness
– Product
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Discoloration
Malodors
Production of gasses that can lead to package swelling or busting
Breakdown in viscosity or elasticity
Otherwise unable to perform as intended
• Types: contact or airborne/ bacterial, yeast or mold
• Resistance to product preservative system or sanitizers
(think antibiotic resistance)
• Classic Microbiology – takes 48-72 h for aerobic bacteria;
72-120 h for yeast or mold
Microbiology – areas of risk
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Heat exchangers
Air compressors
Pumps
Water systems (Grades of water – WFI)
Valves
Ancillary Equipment (O-rings, pipes, clamps, gaskets
Effective Cleaning and Sanitation (C&S)
– Autoclaves, sanitizer, alcohol, steam generators
– CIP – Conducted on assembled equipment
– COP – Conducted on dissembled equipment
Material System
• The measurement and activities to control
finished products, components containers and
closures
– Inventory Control Process
– Drug Storage
– Distribution Controls and Records
• Written procedures for the receipt, storage,
testing and approval or disapproval of raw
materials components, products, containers and
closures
Production System
• Quality and manufacturing process and
procedures (and changes to them) must be
defined, approved and controlled.
• Batch numbering and maintaining proper
traceability is required
– Track batch, equipment use records and labeling used,
personnel, raw material controls are traceable
• Verification of all steps including sign-off are
required for critical process steps.
• All batch records must be reviewed na d have QA
approval before the product is released
Package and Labeling System
• FDA ‘recommends’ as part of the design process
and before commercial products that the controls
for all processes within the packaging and
labeling systems be planned and documented
with written procedures.
– Discriminating features of different
products/strengths
– Distribution of all labels to manufacturing unit
– Reconciliation is performed between label issued,
applied and returned (damaged) to insure 100%
accountability
Laboratory Control system
• Laboratory Controls and written documentation
– Analytical Methods validation and laboratory
equipment qualification
– Scientifically sound stability program to support
labeled expiration dating
– Sampling program Statistical models to determine
sample scheme
– Proper training of QC staff to collect samples
• Batch, water, microbiology, etc.
– Retesting conditions
Critical Elements of Subsystems
• SOPs
– Describes how the company complies with the
drug or device regulations and are critical to GMP
compliance
– See GLP review on overall view of SOPs
– Change Control System – to prevent unintended
consequences to product quality
– Training
– Records
Verification, Qualification and Validation
apply to both Drugs and Devices
• All operational methodologies and procedures
utilized in manufacturing and testing be validated
to demonstrate they can function as intended
• Validation activities must be conducted I
accordance with approved protocols and
appropriate guidances
• Process validation ensures that product quality,
safety and effectiveness are designed and built
into the final product (batch to batch output
uniformity)
Process Validation
• Guidance for Industry: Process Validation: General Principles
and Practices (January 2011)
– Stage 1 – Process Design: The commercial process is based on
knowledge gained through development and scale-up activities
– Stage 2 – Process Qualification: The process qualification is
confirmed as being capable of reproducible commercial
manufacturing
– Stage 3 – Continued Process Verification: Ongoing assurance that
the process remains in a state of control during routine
production. Requires an ongoing program to collect and analyze
product and process data that relate to product quality
(21CFR211.180(e))
• Requires an interdisciplinary team approach (process engineering,
industrial pharmacy, analytical chemistry, microbiology, statistics
• “Begin with the end in mind”
Method Validation
• Draft Guidance for Industry: Analytical
Procedures and Methods Validation – Chemistry
Manufacturing and Controls Documentation
(August 2000)
• Generics - USP
• Each method used to analyze the drug or biologic
must have associated validation to support the
documentation of drug substance, product
identity, strength, purity, and potency
Key GMP Concepts
Key GMP Concepts (cont)
Key GMP Concepts (cont)
IF IT WAS NOT WRITTEN DOWN, THEN IT WAS NOT DONE