Good Laboratory Practices (GLP) and USP 1058 Validation

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Webinar on US FDA Good Laboratory Practices
(GLP) and USP 1058 Validation
Speaker John E. Lincoln J. E. Lincoln and
Associates LLC 2023 by J. E. Lincoln
Associates LLC. All rights reserved.
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AGENDA

• Introduction to the GLPs
• 21 CFR 58
• Pharmaceutical CGMPs, 21 CFR 210 and 211
• Drug QSIT for Key CGMP Sections
• USP 1058, Analytical Equipment Qualification
• QA

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The GLPs

• Scope
• 21 CFR 58 prescribes Good Laboratory Practices
  for conducting nonclinical laboratory studies
  that support or are intended to support
  applications for research or marketing permits
  for products regulated by the Food and Drug
  Administration, including food and color
  additives, animal food additives, human and
  animal drugs, medical devices for human use,
  biological products, and electronic products.
• Compliance with Part 58 is intended to assure the
  quality and integrity of the safety data filed
  pursuant to the Federal Food, Drug, and Cosmetic
  Act and applicable sections of the Public Health
  Service Act.

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Facilities

• Each testing facility shall be of suitable size
  and construction to facilitate the proper conduct
  of nonclinical laboratory studies.
• It shall be designed so that there is a degree of
  separation that will prevent any function or
  activity from having an adverse effect on the
  study.
• As necessary to prevent contamination or mix-ups,
  there shall be separate areas for
• (1) Receipt and storage of the test and control
  articles
• (2) Mixing of the test and control articles with
  a carrier
• (3) Storage of the test and control article
  mixtures.
• Storage areas for the test and/or control article
  and test and control mixtures shall be separate
  from areas housing the test systems and shall be
  adequate to preserve the identity, strength,
  purity, and stability of the articles and
  mixtures.
• Separate laboratory space shall be provided, as
  needed, for the performance of the routine and
  specialized procedures required studies.
• Space shall be provided for archives, limited to
  access by authorized personnel only, for the
  storage and retrieval of all raw data and
  specimens from completed studies.

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Equipment

• Equipment used in the generation, measurement, or
  assessment of data and equipment used for
  facility environmental control shall be of
  appropriate design and adequate capacity to
  function according to the protocol and shall be
  suitably located for operation, inspection,
  cleaning, and maintenance.
• Equipment shall be adequately inspected, cleaned,
  and maintained. Equipment used for the
  generation, measurement, or assessment of data
  shall be adequately tested, calibrated and/or
  standardized per SOP(s).
• SOPs shall set forth in sufficient detail the
  methods, materials, and schedules to be used in
  the routine inspection, cleaning, maintenance,
  testing, calibration, and/or standardization of
  equipment, and shall specify, when appropriate,
  remedial action to be taken in the event of
  failure or malfunction of equipment, and shall
  designate responsibilities.
• Records shall be maintained of all inspection,
  maintenance, nonroutine repairs, testing,
  calibrating and/or standardizing operations.
• Records of nonroutine repairs shall document the
  nature of the defect, how and when the defect was
  discovered, and any remedial action taken in
  response to the defect.

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Facilities / Operations / Changes

• A testing facility shall have SOPs setting forth
  nonclinical laboratory study methods that
  management is satisfied are adequate to insure
  the quality and integrity of the data generated
  in the course of a study.
• All deviations in a study from standard operating
  procedures shall be authorized by the study
  director and shall be documented in the raw data.
• Significant changes in established standard
  operating procedures shall be properly authorized
  in writing by management.
• Each area shall have immediately available
  laboratory manuals and SOPs relative to the
  laboratory procedures being performed. Published
  literature may be used as a supplement to
  standard operating procedures.
• A historical file of standard operating
  procedures, and all revisions thereof, including
  the dates of such revisions, shall be maintained.

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Storage / Retrieval of Records / Data

• All raw data, documentation, protocols, final
  reports, and specimens (except those specimens
  obtained from mutagenicity tests and wet
  specimens of blood, urine, feces, and biological
  fluids) generated as a result of a nonclinical
  laboratory study shall be retained.
• There shall be archives for orderly storage and
  expedient retrieval of all raw data,
  documentation, protocols, specimens, and interim
  and final reports.
• Conditions of storage shall minimize
  deterioration of the documents or specimens in
  accordance with the requirements for the time
  period of their retention and the nature of the
  documents or specimens.
• A testing facility may contract with commercial
  archives to provide a repository for all material
  to be retained.
• Raw data and specimens may be retained elsewhere
  provided that the archives have specific
  reference to those other locations.
• An individual shall be identified as responsible
  for the archives.
• Only authorized personnel shall enter the
  archives.
• Material retained or referred to in the archives
  shall be indexed to permit expedient retrieval.

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Disqualification of Testing Facility

• The FDA may disqualify a testing facility upon
  finding all of the following
• The testing facility failed to comply with one or
  more of the regulations set forth in this part
  (or any other regulations regarding such
  facilities)
• The noncompliance adversely affected the validity
  of the studies and
• Other lesser regulatory actions (e.g., warnings
  or rejection of individual studies) have not been
  or will probably not be adequate to achieve
  compliance with the good laboratory practice
  regulations.
• Once a testing facility has been disqualified,
  each application for a research or marketing
  permit, approved or not, containing or relying
  upon any study conducted by the disqualified
  testing facility may be examined to determine
  whether such study was or would be essential to a
  decision. If so, the FDA shall also determine
  whether the study is acceptable, notwithstanding
  the disqualification of the facility.
•  The FDA may refer the matter to another Federal,
  State, or local government law enforcement or
  regulatory agency for any action.
• The FDA may refuse to consider any study, if it
  finds it was not conducted in accordance with the
  GLPs, without disqualifying the testing facility.
• A disqualified facility can be reinstated upon
  proof of compliance to the GLPs.

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Drug CGMPs, 21 CFR 210 / 211

• 210.1 Status of CGMP Regulations
• (a) The regulations set forth in this part
  contain the minimum current good manufacturing
  practice for methods to be used
• (b) The failure to comply with any regulation
  set forth in this part and in parts 211 through
  226 of this chapter in the manufacture,
  processing, packing, or holding of a drug shall
  render such drug to be adulterated such drug,
  as well as the person who is responsible for the
  failure to comply, shall be subject to regulatory
  action.

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Drug CGMP Elements, 21 CFR 211

• Subpart A- General
• B- Organization and Personnel
• C- Buildings and Facilities
• D- Equipment
• E- Control of Components
• F- Production and Process Control
• G- Packaging and Labeling Control
• H- Holding and Distribution
• I- Laboratory Controls
• J- Records and Reports
• K- Returned and Salvaged Drug Products
• 11 elements

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Key Drug CGMP Elements
US FDAs QSIT - a model

• For Medical Devices, but similar emphasis with
  the other industries
• Quality System Inspection Technique (devices but
  note principles for all GMP systems)
• Guidance for inspecting medical device
  manufacturers against the Quality System
  Regulation (21 CFR Part 820) and related
  regulations.
• Distills the 15 subparts of 21 CFR 820 into 7,
  then 4 key areas (with linkages / ties to others)
  
• Top-down (vs. old bottoms up)
• Subsystem approach
• Pre-announced inspections.

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2. Design Controls

• Key Issues (adapt to Drugs / Formulation
  Controls)
• SOP defined / followed
• Development of new / changed product under design
  control, documented
• Preparation of Risk Management Files per ISO
  14971 (or ICH Q9)
• Preparation of Human Factors / Use Engineering
  Files per IEC 62366-1
• All product changes documented (DHF, DMR, change
  control )
• Changes verified / validated, monitored
• Compilation / maintenance of the Design History
  File or comparable documentation
• Comparable pharma / dietary supplements lab
  controls / production monitoring / controls

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3. CAPA

• Key Issues
• SOP defined / followed
• Timely
• Documented
• Closed loop
• Failure Investigations
• Root Cause Analysis
• Verified / validated
• Monitored, revisited
• Trended

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4. P PC

• Key Issues
• SOP defined / followed
• HACCP principles employed
• Calibrated instrumentation
• PM program
• SOP defined
• Verified / validated
• All software / firmware validated
• E-CGMP systems validated, including to 21 CFR
  Part 11
• Statistical controls / trending GRR Cpk
• See QSIT Guidance Document for more inspection
  questions / flow charts.

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Basic Purpose of VV

• Not just compliance
• Dont miss the forest (purpose of VV) for
  the trees (definitions,
• mechanics of VV)
• To prove that the system being VVd does what
  it is expected to do
• When installed properly (IQ)
• With settings / parameters optimized (OQ)
• With worst case inputs (PQs)
• Repeatedly (PQs)
• Without any surprises (i.e., doesnt do what it
  shouldnt do
• PQs).

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Qs, V V

• Throughout this presentation the following
  working definitions will be used (to be fully
  explained later)
• Verifications Tests, Checks, Inspections, most
  Qualifications Verifications are performed
  against Requirements
• Validations A collection of verifications /
  qualifications, to prove all Requirements have
  been met.
• Requirements Marketing, Manufacturing /
  Engineering, Standards, Regulatory, Guidance
  Documents, Specifications, etc.

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Verification or Validation?

• Working Definitions
• Verification Inspection, testing or checking
  most qualifications
• Decommissioning Product Verification Design
  Output Design Input.
• Validation A series of verifications may
  involving destructive
• testing
• Product Validation Customer Requirements
  Resultant Product
• Process / Equipment / Facility DQ, IQ, OQ, PQ
• Software In-product, As-product, Process /
  Equipment 11
• elements (U.S. FDA guidance model)
• Software QMS 21 CFR Part 11 ER / ES
• Site -Qualification
• Commissioning
• FAT SAT
• Master Validation Plan or Validation Master Plan
• Protocols the whole document, or just the
  test portion.

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VV Hierarchy
Verification and Validation Planning activity
and Development of the Validation Master Plan
controlled document And Related SOPs
controlled documents Proceed Somewhat
Concurrently Then Develop A Specific Validation
Plan for each Item to be VVd part of the Test
Report, a formal document Then Run The
Validation And Compile the Validation Test
Report.
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The Validation Master Plan

• Or Master Validation Plan
• Corporate, Site, Process / Product Family
  Products, Process /
• Equipment, Test, Software Systems
• Life cycles concept through decommissioning
• Risk-based (ISO 14971/device
  Q9/drugs/biologics)
• Product VV Actual Product / Output Market
  Requirements / Input
• Equipment / Process VV DQ, IQ, OQ, PQs
• Software As product
• In product
• Equipment / Process
• QMS (21 CFR Part 11)
• Revalidation (on demand, not scheduled /
  periodic)

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Training

• Training to the GLPs should cover the information
  just discussed
• Develop the Lesson Plan
• Publish the Agenda, including Description,
  Location, Duration, Instructor
• Have an SOP and Training and a Record of
  Attendance (Attachment?)
• Conduct training (quiz with grading recommended)
• Attendees sign Record of Attendance
• Follow-up recommended
• Copies of Attendance and Agenda in personnel
  files.
• Enhance with CAPA findings and CGMP/GLP audit
  findings.
• CGMP / GLP training should be periodic / annual.

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Course Disclaimer
The information provided in this workshop is
taken from sources and material which we believe
to be reliable, and/or express the opinions of
the writers and/or presenter. In such condensed
and generalized form, the material certainly
should not be considered a complete study or
report on the subject mater, especially as to how
it might relate to a specific company / users
application. Conclusions are based solely on
available data, and the judgments and analysis of
technical factors offered are not intended to
replace the utilization of additional research
and/or appropriate professional counsel in
adapting material to a specific application.
2023 by J. E. Lincoln Associates LLC. All
rights reserved. Reproduction in whole or in
part without written permission is prohibited.
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Q A

• This is the chance to address issues that may not
  have been covered to your satisfaction or
• To expand a point or
• To clarify a point.
• If there are any further questions which we were
  not able to get to today please feel free to
  contact me directly.