Overview of Regulatory Requirements for API and · PDF fileOverview of Regulatory Requirements...

Overview of Regulatory Requirements

for API and Formulations

Sangeeta Sardesai

4-Dec-2010

7-Dec-10 Sangeeta Sardesai - sanofi aventis 2

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.


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)


Systems covered

� Quality System

� Facilities and Equipment System

� Materials System

� Manufacturing System

� Packaging and Labelling System

� Laboratory Control System

� Information System.


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


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


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


� 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


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



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



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)



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



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


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


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


Materials System

� Supply Chain evaluation

� Supplier Evaluation

� Criticality of material

� Transportation requirements

� Purchased against agreed specification

� Change control process for changing suppliers


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


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.)


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


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


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


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



� 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



� 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


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


Most Common GMP Deficiencies by System

Laboratory

17%

Production

10%

Facilities and Equipment

15%

Materials

5%

Quality

41%

Packaging and Labeling

13%


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


Questions ????

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