Overview of Regulatory Requirements
for API and Formulations
Sangeeta Sardesai
4-Dec-2010
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Definition - Regulatory Requirement
The restrictions, licenses, and lawsapplicable to a product or business, imposed by the government.
� Regulatory requirements describe what is
necessary for a new drug to be approved for
marketing in any particular country.
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Various Regulatory Agencies-
� Drugs and Cosmetics Act, 1940 and Drugs and Cosmetics Rules,
1945 - India
� Food and Drug Administration (FDA) – US
� European Medicines Agency (EMA) – EU
� Medicines & Healthcare products Regulatory Agency (MHRA)-UK
� Therapeutic Goods Administration (TGA) – Australia
� Pharmaceutical and Medicines Agency (PMDA) – Japan
� Health Canada - Canada
� World Health Organisation (WHO)
� International Conference on Harmonization (ICH)
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Systems covered
� Quality System
� Facilities and Equipment System
� Materials System
� Manufacturing System
� Packaging and Labelling System
� Laboratory Control System
� Information System.
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State of Control
� Detailed inspection of a system so that the findings reflect the
state of control in that system for every product (profile) class
� If one of the six systems is out of control, the firm is
considered out of control
� A system is considered out of control based on GMP
deficiencies which suggest lack of assurance of quality
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Quality System
� Assures overall compliance with cGMPs and internal procedures
and specifications.
� Includes Quality Control Unit and all of its review and approval
duties
� Quality Unit which is independent from Production
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Quality System
� Includes-
� Batch Release
� Product Quality Reviews
� Complaint reviews
� Discrepancy/ failure investigations
� Change Control
� CAPA (Corrective And Preventive Action) Reprocess/ Rework
� Validation/ Revalidation
� Rejects
� Stability Failures/ Out of trend data
� Quarantine products
� Documented GMP & Job Related Training
� Reprocessed, reworked, returned, salvaged product
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� Includes measures and activities which provide an appropriate
physical environment and resources used in the production of
the drugs or drug products.
� Facilities
� Equipment
� Utilities
� HVAC
� Water System
� Separate facilities or containment where needed (penicillins,
highly potent compounds etc.)
Facilities & Equipment System
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Facilities & Equipment System-
Facilities
� Location, design, construction appropriate to facilitate
cleaning, maintenance, operations
� Prevent cross-contamination
� Layout and air handling design and construction
� Containment
� Positive / Negative pressures as required by product
� Flow of materials & personnel
� Linear and uni-directional
� Adequate space for placement of equipment and materials
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Facilities & Equipment System-
Facilities
� Defined areas and other control systems
� Quarantine (intermediates, APIs)
� Released materials
� Rejection areas
� Sampling / Dispensing areas
� Production operations
� Packaging and labeling operations
� Laboratory operations
� Adequate washing and toilet facilities
� Separate gowning areas – primary / secondary
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Facilities & Equipment System-
Equipment
� Appropriate design, size, location, non-reactive product contact
surfaces
� Identification clearly marked
� Qualification (DQ, IQ,OQ, PQ)
� Calibration – Schedule, procedures and records
� Preventive Maintenance – Schedule, procedures and records
� Regular checks
� Cleaning procedures and validation (CIP / SIP)
� Records of use, cleaning, maintenance
� Lubricants, heating fluids or coolants (not contact/alter product
quality)
� Closed or contained equipment (where required)
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Facilities & Equipment System-
Utilities (HVAC & pipelines)
� Designed and constructed to prevent contamination / cross-
contamination
� Drawings should be available
� Qualification / Validation / Calibration
� Routine cleaning / replacement / maintenance
� Regular testing
� Trends – Alert / Action Limits
� Permanently installed pipework should be appropriately
identified
� Drains of adequate size with air break
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Facilities & Equipment System-
Water� Process water at minimum meeting WHO guidelines for potable
water
� Justify quality of water used to achieve stated Quality
� Qualified / Validated Water systems
� Regular program for sanitization
� Established specifications
� Testing at fixed intervals – Chemical / Microbiological
� Trends – Alert / Action levels
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Materials System
� Includes receipt, Identification, storage, handling, sampling,
approval / rejection of raw materials, components, drug
product containers and closures
� Handling and Storage Requirements
� Preference for computerized inventory control processes
� Handling and storage to prevent degradation, contamination and
mix-up
� Separate storage space for Quarantine and Approved
� Appropriate storage conditions (Freezer, Cold storage etc.)
� Appropriate identification at all stage of storage and usage
(Quarantine, Under Test, Approved, Rejected)
� Separate access-restricted area for rejected / return goods
� Cartons, bags, boxes off the floor, away from walls
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Materials System
� Sampling / Dispensing
� Representative sampling – Statistically based
� Written sampling plan with justification
� Sampling to prevent contamination / cross-contamination
� Identification of sampled containers
� Re-evaluation / Retest Date
� First In, First Out / First Expired, First Out – FIFO / FEFO
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Materials System
� Supply Chain evaluation
� Supplier Evaluation
� Criticality of material
� Transportation requirements
� Purchased against agreed specification
� Change control process for changing suppliers
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Manufacturing System
� Includes measures and activities to control the manufacture of
drugs and drug products.
� Training (documented; job-related)
� Batch Documentation
� Master & Batch production and control records
� Accurate and complete batch production documentation
� Implementation and documentation of in-process controls, tests
� Adequate written procedures & practice
� Identification of equipment with contents, stage of
manufacturing, status
� Equipment usage and cleaning records
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Manufacturing System
� Manufacturing Process
� To ensure prevention of contamination and cross-contamination
� Established time limits for completion of production steps/ stages
� Critical weighing and manufacturing operations should be witnessed
� Justification and consistency of in-process specifications and final
product specifications
� Process validation based on knowledge of process – Identify CPP
� Yields should be calculated – Deviations should be documented and
investigated
� Reprocessed / Reworked materials should be appropriately
controlled.
� Data/ information documented and available to Quality Unit for
review (trending, investigations etc.)
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Packaging and Labeling System
� Includes measures and activities that control the packaging
and labeling of drugs and drug products.
� Process Validation
� Written procedures for-
� Receipt, identification, quarantine, sampling, examination
and/or testing
� Reconciliation; investigation if discrepancy
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Packaging & Labeling System
� Packaging Operations
� Packaging and labeling areas must be designed to prevent mix-up
and cross-contamination.
� Access to label storage area limited
� Controls / procedures in place for packaging and labeling
operations
� Adequate identification of labeling and packaging materials
� Documented procedures to ensure correct packaging materials
and labels are used
� Examination of labeling and packaging materials prior to use
� Line clearance
� Stereo Controls
� Control on over-printing / embossing
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Packaging & Labeling System
� Records / Documents-
� Approved Specifications - should conform to specifications
� Master and Batch Packing Records
� Print labels checked against master and a copy placed into the
batch record
� Records maintained for each shipment (showing receipt,
examination & result)
� Destruction -
� All printed packaging and labels with batch number to be
destroyed at site.
� Obsolete labels to be destroyed at site
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Laboratory Control System
� Includes measures and activities related to laboratory
procedures, testing, analytical methods development,
validation / verification, stability program
� Adequate laboratory facilities
� Adequately staffed laboratories (supervisory and bench personnel)
� Qualified and trained
� Reference Standards (primary; secondary)
� Microbiological cultures
� Instrumentation as per testing requirements
� Adequate Microbiology facility to support the site requirements
� Qualified Microbiologist
� Retention Sample Handling and Controls
� Stability Management Program
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Laboratory Control System
� Written Documents-
� Approved specifications
� Approved procedures for sampling, testing, approval / rejection
� Trending – OOT
� Laboratory controls followed and documented
� Out of Specifications (OOS)
� Approved procedure (SOP) covering OOS
� Investigation of “OOS” results in a timely manner as per SOP and
documented. CAPA identified and implemented.
� “OOS” review included in Product Quality Reviews
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Laboratory Control System
� Validation / Qualification
� Method validation/ revalidation
� Equipment Qualification / Maintenance - AMC
� Calibration: written procedures, schedule, documentation - OOC
� Validation and Security for computerized handling of test results
and related data
� Excel sheet usage and validation
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Systems Approach Goal
Evaluate whether management Evaluate whether management Evaluate whether management Evaluate whether management
with executive responsibility with executive responsibility with executive responsibility with executive responsibility
ensures that an adequate and ensures that an adequate and ensures that an adequate and ensures that an adequate and
effective quality system has been effective quality system has been effective quality system has been effective quality system has been
established and maintainedestablished and maintainedestablished and maintainedestablished and maintained
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Most Common GMP Deficiencies by System
Laboratory
17%
Production
10%
Facilities and Equipment
15%
Materials
5%
Quality
41%
Packaging and Labeling
13%
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GMP Guide for API (ICH Q7)
� Provides guidance regarding good manufacturing practice (GMP)
for the manufacturing of active pharmaceutical ingredients
(APIs) under an appropriate system for managing quality.
� Intended to help ensure that APIs meet the requirements for
quality and purity
� Applicable to all APIs manufactured by chemical synthesis,
extraction, cell culture / fermentation (separate section)
� Not applicable to sterile APIs, vaccines, whole blood and plasma,
gene therapy APIs
� More Widely used by Regulators worldwide
� EU Volume 4 – Part II – Basic requirements for Active substances
used as starting materials
� WHO, TRS No. 957, 2010 – Annex 2- WHO GMP for API
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Questions ????