Transcript Slide 1 - Pharmexcil - Pharmaceuticals Export Promotion

Presentation by:
Dr. A. Ramkishan
Asst. Drugs Controller (India)
Govt. of India
“Good Laboratory Practices and
Requirements of Premises & Equipments”
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Seminar Overview
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Schedule L-I notification and D & C Act Rules
Management
and
Infrastructure
(Organization
&
Management, Premises, Personnel, Equipments)
Materials, Equipments, Instruments
& Other Devices
(Chemicals & Reagents, Good Housekeeping & Safety,
Maintenance, Calibration & Validation of Equipments,
Reference Materials/Substances, Microbial Cultures)
Quality Management System
Working Procedures (SOPs, Protocols & Specifications
Archive, Raw data, Storage & Archive)
Internal Quality System Audits
Management Review
Safety (General Rules)
India Advantage & Challenges
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Evolution of Indian Drug Legislation
Objective
The Objective of Drugs & Cosmetics Act 1940 is to ensure that
public are supplied with Quality, Purity, Identity, Safety and
efficacy of Pharmaceutical Products & Cosmetics.
Basic Philosophy
The basic philosophy of Drugs & Cosmetics Act is that the
manufacturer is responsible for the quality of drugs
manufactured by them and the Government/Regulatory
Agencies will monitor the quality of drugs by periodic
inspections of the manufacturing and sales premises for
confirmation to the provisions of Drugs & Cosmetics Act and
monitoring the quality of drugs moving in the market by
carrying out post market surveillance.
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Evolution of Indian Drug Legislation Cont..
Principle
The principle on which the Drugs & Cosmetics Act function is by
a system of licensing under which all the activities involved in
manufacture, sale and distribution of Drugs & Cosmetics are
controlled.
Drug regulatory system in India
Drug is in concurrent list of Indian Constitution. It is governed
by both Centre and State Governments under the Drugs &
Cosmetics Act 1940 & Rules 1945 there under.
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Functions of CDSCO
Functions of CDSCO
Approval of new drugs and clinical trials
Import Registration and Licensing
Licensing of Blood Banks, LVPs, Vaccines, r-DNA
products & some Medical Devices
Amendment to D &C Act and Rules
Banning of drugs and cosmetics
Grant of Test License, Personal License, NOCs for Export
Testing of Drugs
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Functions of State Licensing Authorities
Functions of State Licensing Authorities
Licensing of Manufacturing Site for Drugs including API and
Finished Formulation
Licensing of Establishment for sale or distribution of Drugs
Approval of Drug Testing Laboratories
Monitoring of Quality of Drugs and Cosmetics marketed in the
country
Investigation and prosecution in respect of contravention of
legal provision
Recall of sub-standard drugs
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CDSCO – Geographical Location of 6 Zonal Offices
CDSCO, HQ
CDSCO North Zone (Ghaziabad)
CDSCO West Zone (Mumbai)
New Delhi
CDSCO South Zone (Chennai)
Ahmedabad
CDSCO East Zone (Kolkata)
New Zonal Offices –
Ahmedabad & Hyderabad
Sub- Zonal Offices
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Port Offices/Airports : 7
Laboratories
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Kolkata
Mumbai
•* Hyderabad
Chennai
29 States
6 Union Territories
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Evolution of Indian Drug Legislation Responsibilities Cont..
Joint Responsibilities of CDSCO &
SLAs
Licensing of Specialized
Products
Vaccines &
Sera
Blood & its
Components
LVPs
r-DNA
Products
Medical
Devices
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Implementation of Schedule L-I
 The draft GLP published dated 13th October 2006 inviting
objections & suggestions from Stake holders.
 And, whereas, objections and suggestions received from the
public on the said draft rules have been considered by Govt.
of India.
 Now therefore, in exercise of the powers conferred by the
sections 12 & 33 of D & C Act, the Central Government after
consultation with the DTAB, hereby made the rules called as
D & C (3rd amendment) Rules 2008.
 The Drugs and Cosmetics Rules were amended to incorporate
Schedule L-I on GLP and Requirement of premises and
equipments published under notification GSR 780 (E) dated
10th November 2008 (File No. X-11014/3/2006-DFQC).
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Implementation of Schedule L-I Cont..
 A period of two years was granted for the Pharma industry to make
necessary arrangement to comply with the requirement of Sch. L-I
before these are made mandatory.
 Accordingly the notification mentioned that these Rules will be
effective from first day of November, 2010.
 The labs are required to comply all the GLP norms mentioned in the
Schedule L-I of D & C Act a per Rule 74, 78 & 150-E to cover quality
system/SOPs, equipment calibration/validation, reference materials,
reagents, staff, testing procedures, results record & computerization,
personnel & environmental safety, data integrity, including archiving.
 Internal quality system audits are required to put in practice to verify
that the operations conduct in the laboratories comply with the
requirements of quality system.
 State licensing authorities may ensure that the provisions under Sch.
L-I are implemented in the testing laboratories set up by the
manufacturers for in house testing and approved testing laboratories.
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D & C Act 1940 and Rules there under
 Schedule L ,1979-rule 65(9) GSR 1241 dated 15.09.1979 & 97
GSR 592 (E) dated 13.08.2008 are omitted.
 Schedule L-I 2008 (3rd amendment) prepared on GLP for
various labs covered the rules- 74,78 & 150-E of D & C Act .
 Rule 74 (GSR 218 (E) dated 28.03.2001) deals with condition of
license {Form 25 (other than C, C1 & X drugs) & 25-F (Sche. X
Drugs)}.
 Rule 78 (GSR 462 (E) 26.06.1982 & omitted, revised w.e.f.
01.11.2010) deals with conditions of license {Form 28 (for C &
C1 Drugs excluding Sche. X) , 28-B (for C, C1 & X Drugs) or
26-D (renewal of Lic. for AUSH Drugs)}.
 Rule 78(p) deals with compliance of GLP & GMP.
 Rule 78(m) deals with reference samples for proper storage
 Rule 150-E deals with conditions of approval
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D & C Act 1940 and Rules there under cont..
 Rule 150-B deals with application for grant of approval for testing
drugs/cosmetics in Form 36.
 The labs shall be made an application in Form 36 to SLA for
necessary approval with fees Rs.6000/- for C,C1 drugs and Rs.1500/for other than C&C1 drugs/Cosmetics (as per Rule 150-B).
 Rule 150-C deals with approval for carrying out such tests of
identity, purity, quality & strength of drugs or cosmetics shall be
granted in Form 37.
 An approval granted in Form 37 or renewed in Form 38 unless
sooner suspended or withdrawn shall be valid for a period of five
years on and from the date on which it is granted or renewed (Rule
150-D).
 The approved institution shall furnish reports of the results of tests
or analysis in Form 39 as per Rule 150-E of D & C Act 1940.
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D & C Act 1940 and Rules there under cont..
 Inspection before grant of approval
(Rule 150-F) and
inspection team consisting of CDSCO & SLA, who shall
examine the premises, equipments, staff, testing procedures
intended to be used for testing of Drugs & Cosmetics.
 Rule 150-G deals with report of inspection
 Rule 150-H deals with procedures of approving authority
(SLA) shall grant an approval in Form 37.
 Rule 150-J deals with renewal of approval in Form 38
 Rule 150-K deals with suspension & withdrawal of approvals
 Rule 150-I deals with further application after rejection in
Form 37
 A Licensee (PTL/Group/National/QC labs) shall maintain an
inspection book in Form 35 to record the observations if any
by the FDA/CDSCO inspectors.
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Definition of GLP
 Good Laboratory Practice (GLP) deals with the organization, process
and conditions under which laboratory studies are planned, performed,
monitored, recorded, reported & archived. GLP practices are intended
to promote the quality and validity of test data (part 58 CFR 21). OR
 GLP is a quality system concerned with the organizational process and
the conditions under which non clinical health & environmental safety
studies are planned, performed, monitored, recorded, archived &
reported. (Ref. Jurg P. Seiler-Switzerland, GLP, 2nd edition by Springer
publication, 2005, Page 61).
 Schedule L-I regulations and guidelines have a significant impact on the
daily operation of an analytical laboratory.
 GLP is a regulation. It is not only good analytical practice. Good
analytical practice is important, but it is not enough. For example, the
laboratory must have a specific organizational structure and procedures
to perform and document laboratory work. The objective is not only
quality of data but also traceability and integrity of data. But the biggest
difference between GLP and Non-GLP work is the type and amount of
documentation.
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Definition of Quality Control
 Quality Control Laboratory: All measures taken, including
the setting of specifications, sampling, testing and analytical
clearance, to ensure that raw materials, intermediates,
packaging materials and finished pharmaceutical products
conform with established specifications for identity, strength,
purity & other characteristics.
 Quality:- The degree to which a set of inherent properties of a
product, system or process fulfills requirements. (ICH Q6a)
 Risk:- The combination of the probability of occurrence of
harm & the severity of that harm (ISO/IEC Guide 51)
 Harm:- Damage to health, including the damage that can
occur from loss of product quality or availability. Whereas
hazard is the potential source of harm & severity is a measure
of the possible consequences of a hazard
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Role of GLP Inspectors
 For a FDA/CDSCO inspector it should be possible to look at
the documentation and to easily find out
 who has done a drug sample testing,
 how the sample testing was carried out, which procedures have been used, and
 whether there has been any problem and if so
 how it has been solved.
 The FDA inspectors should look at the possibility for a third
party to reconstruct the whole drug samples testing plan &
second issue can be looked at as accountability for mistakes of
above plan & thirdly GLP increases awareness for quality and
transparency of the analysis of different samples conducted at
their laboratory.
 GLP Compliance as per Schedule L-I of Drugs & Cosmetics
Act.
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Role of GLP Inspectors Cont..
 Basic research, Disease Discovery & Drug Discovery are not
regulated for GLP.
 The GLP regulation starts from Pre-clinical development to
QC Laboratories.
 Clinical trials are regulated by good clinical practice
regulations and manufacturing through GMPs.
 Characteristic for GLPs is that they are study based where as
GMPs are processed based
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Elements of GLP
 To a large range of laboratory related issues that can shortly
be characterized as follows
1- Laboratory infrastructure and personnel.
2- Laboratory methodologies & reference values.
3- Laboratory equipment & maintenance.
4- Test result records & computerization.
5- Quality system (internal audits, management review).
6- Function of annual units and experiments.
7- SOPs & General safety.
8- Storage and archival.
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Organization & Management
 The laboratory or the organization of which it is a part must be
an entity that is legally authorized to function & can be held
legally responsible.
 It is the responsibility of the management to ensure that the
laboratory carry out its testing, calibration, validation & all other
technical activities in such a way as to meet GLP requirements as
per Schedule L-I
 The laboratory should be organized and operate so as to meet
the requirements of Schedule L-I.
 The laboratory should have a qualified individual to be known
as quality manager or technical manager with the authority and
resources needed for carrying out all technical activities and for
the implementation of documented quality system to report
directly to top management.
 The quality manager shall prepare a Schedule for technical audit
of lab for GLP compliance as per quality manual.
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Premises
 The laboratory facilities shall be designed, constructed and
maintained so as to prevent entry of insects and rodents besides
cross contamination.
 The lab interior surface (walls, floor and ceilings) should be smooth
and free from cracks and permit easy cleaning/disinfection.
 Adequate area should be provided for equipments for carrying out
different tests but also for utilities like water, gas and power.
 The lab should have air ventilation system to ensure dust free
environment.
 The lab should be provided with adequate lighting and ventilation
and if necessary AC to maintain proper temperature/Rh that will
not effect the testing and storage of drugs or accuracy functioning of
equipments.
 The lab should have proper drainage system to avoid water logging.
 Tabletops shall be constructed with acid, alkali and solvent resistant
material (Free from crevices).
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Premises Cont..
 All the laboratory waste material generated, before, during &
after testing of different pharmaceutical products/cosmetics
should be destroyed as per Bio-Medical waste rules 1996
(management & handling).
 The laboratory should ensure that environmental conditions
are monitored, controlled & documented.
 Adequate area should be provided for storage of reference,
working standards & thereof specific SOP should be prepared
by the laboratory.
 If the laboratory engaged with microbiological testing, BET
testing & sterility testing should meet the requirements of air
circulation (HVAC system) with requisite class condition as
per the revised Schedule M of D & C Act 1940.
 The bio burden levels should be routinely monitored in the
airlocks provided for controlled & un-controlled areas.
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Premises Cont..
 The Lab should have proper area for animal house and
should have the approval of the Committee for the Purpose of
Control and Supervision on Experiments on Animals
(CPCSEA) from regional office of ethics animal committee.
 The lab should have proper segregation for quarantine the
new animals procured are purchase and have a provision for
clean corridor and dirty corridor.
 The disease animals shall be properly diagnosed with proper
record of their treatment.
 Different types of animals should be housed separately with
proper identification.
 The Lab should have air conditioner (AC) for animal house
(Temp./RH).
 The Animal house should be isolated from the laboratory
with separate entrance if applicable.
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Personnel
 The laboratory should have sufficient staff with necessary
qualification, training, experience for their assigned functions
and thereof training records are maintained.
 The head of the laboratory must be off high professional
standing with experience for testing of drug samples & lab
management is responsible for ensuring control and
maintenance of documents including quality system.
 The laboratory should have proper planning and organizing the
audit of quality system to take care of CAPA.
 CAPA resulting from the investigation of complaints, product
rejections, non conformances, recalls, deviations, audits,
regulatory inspections & findings, trends from process
performance & product quality monitoring. The objective of
CAPA is determining the root cause of deviation.
 Corrective Action: Action to eliminate the cause of a detectable
non-conformity or other undesirable situation. Note: Corrective
action is taken to prevent recurrence whereas preventive action
is taken to prevent occurrence (ISO 9000:2005)
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Personnel cont…
 Preventive Action: Action to eliminate the cause of potential
non-conformity or other undesirable potential situation.
Note: Preventive action is taken to prevent occurrence
whereas corrective action is taken to prevent recurrence (ISO
9000:2005).
 The laboratory should have proper planning for investigation
of technical complaints including NSQ reports for regulatory
action.
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Equipments
 The laboratory should have the required equipments for
carrying out the different activities within the lab.
 The analytical instruments should be kept in dust free
environment with proper control of temperature and
humidity.
 The equipment should be kept under hygienic conditions and
tidy (logical/orderly/arranged/uncluttered) at all times.
 The laboratory should have proper calibration plan and
validation plan for equipments provided to carry out at
specified regular intervals and records of such
calibration/validation reports be maintained.
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Equipments cont...
 The records should be maintained for all the equipments consisting of:
I. Name of Equipment or Machine or Apparatus;
II. Manufacturer’s name, Model number and type of identification;
III. Serial number;
IV. Date on which equipment was received in laboratory;
V. Current location;
VI. Condition when received (e.g. new, used, re-conditioned)
VII. Copy of the manufacturer’s operating instructions;
VIII. Frequency of calibration;
IX. Frequency of maintenance;
X. Log Book (Day to day entry including status of the equipment)
XI. Staff responsible for monitoring the calibration and maintenance status of the
equipment;
XII. Calibrating records;
XIII. List of authorized users or operators, if any;
XIV. History of any damage, malfunction, modification or upgradation, repair and
calibration;
XV. List of spares and accessories, if any;
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Equipments cont...
 The laboratory should have separate register for defective
equipments and also spare/accessories.
 The lab. should have respective SOP’s for operation, performance,
calibration & maintenance of equipments.
 The lab. should have thorough checks for accuracy of important
items like; burettes, pipettes, volumetric flasks, weight boxes,
thermometers, etc., before use.
 The lab. Should have competent person for handling and
maintenance of equipments for services like; electricity, gas, water,
steam and compressed air, etc.
 The lab. should have well defined area for handling of hazardous
solvents, reagents and chemicals with proper exhaust system and
drainage system to avoid water logging inside the fume cupboard.
 The lab. Should have proper log books, calibration chart reports,
validation
reports,
engineering
requisition
slips
for
repair/modification if any, CAPA system, change management
system and equipments service record’s.
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Chemicals & Reagents
 The laboratory should have proper plan for storage and
handling of chemicals and reagents while preparing by taken
into the consideration of Physico-chemical properties with
proper status label.
 Register should be maintained for standardization of stock
solutions, standard solutions & volumetric solutions etc.
 All the above said chemicals/ reagents should be off appropriate
quality if required the Lab head must insist the COA, MSDS &
reputation of suppliers in the market for their quality standards.
 The labeling should be appropriate to meet the parameters like
concentration, strength, storage condition, date of preparation,
use before, standardization factor, sign of chemist etc.
 Visual inspection is carried out for reagents if applicable.
 Water should be considered as a reagent & appropriate water
grade for specific test should be used as described in the various
Pharmacopoeias or in approved tests when available.
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Good House Keeping and Safety
 Lab should prepare adequate poster displays, audio visual
material, & conduct seminars and conferences for safety aspects.
 Safety Data sheets must be available before testing is carried out.
 Drinking, eating, smoking shall not be permitted in lab.
 Laboratory staff must wear protective clothing including gloves,
facemasks & eye protection when ever required.
 Lab should be equipped with adequate number of fire
extinguishers, fire blankets and gas masks etc. and also first aid
kit.
 Adequate training is must for staff for handling of safety
equipments (emergency care and use of antidotes, handling
cylinders of compressed gases).
 Lab should have well defined SOP for safety, housekeeping,
training, disposal of wastes (chemicals and biological), handling
of corrosive materials (Hg, KCN, CNBr), infectious agents,
mixing of water with Acids etc.
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Maintenance, Calibration & Validation of Equipments
 Maintenance: A procedure of inspecting, testing, and reconditioning a
system at regular intervals according to specific instructions, intended to
prevent failures in service or to retard deterioration.
 Calibration: The process of determining the performance parameters of
an artifact (object) , instrument, or system by comparing it with
measurement standards (Accuracy & Precision).
 Validation: Action of proving and documenting that any process,
procedure or method actually and consistently leads to the expected
results.
 Validation vs. Qualification: The term qualification is normally used for
equipment, utilities and systems, validation is normally used for
processes in this sense, qualification is the part of validation.
 Validation should be performed for new premises, equipments, utilities,
systems, procedures & processes at periodic intervals & when major
changes have been made.
 Risk assessment approach should be used to determine the scope &
extent of validation required.
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Maintenance, Calibration & Validation of Equipments Cont..
 Qualification: Action of proving & documenting that any
analytical equipment complies with the required
specifications and performs suitably for its intended purpose.
 The lab should have well defined SOP, qualification protocols,
calibration schedule, appropriate methods and procedures for
all tests or calibrations.
 The lab should have records for calibration of equipments and
other required documents including log books.
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Quality management system
 QMS: An appropriate infrastructure, encompassing the
organizational structure, procedures, processes and resources,
and systematic actions necessary to ensure adequate
confidence that a product or service will satisfy given
requirements for quality.
 Quality System: Aggregate of the organizational activities,
incentives, plans, policies, procedures, processes, resources,
responsibilities, and the infrastructure required in
formulating and implementing a total quality management
(TQM) approach in a testing laboratory.
 Quality Manual: A handbook that describes the various
elements of the quality management system for assuring the
quality of the test results generated by a laboratory.
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Reference materials
 Reference material: Material sufficiently homogeneous and stable
with respect to one or more specified properties, which has been
established to be fit for its intended use in a measurement processes .
 Reference substance (or standard):An authenticated, uniform
material that is intended for use in specified chemical and physical
tests, in which its properties are compared with those of the product
under examination, and which possess a degree of purity adequate
for its intended use .
 Primary reference substance (or standard): A substance that is
widely acknowledge to possess the appropriate quality within the
specified context, and whose assigned content is accepted without
requiring comparison with another chemical substance.
 Secondary reference substance (or standard):A substance whose
characteristics are assigned and/or calibrated by comparison with a
primary reference substance may be less than for a primary
reference substance Note: often referred to as an “in-house” working
standard.
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Reference materials cont…
 The lab should have necessary above said materials for testing,
calibration, validation & verification of a sample or equipment or
instrument or devices and such materials should be traceable to
agency authorized by Govt. of India or international body.
 The lab should prepare working standards by comparing with
reference standards and shall be routinely checked for their purity,
identity, loss on drying or on water, impurity and assay etc. thereof
register should be maintained containing the details like source of
supply, code number of reference material, date of receipt, batch
number, storage condition, date of expiry, date of mfg. and other
details like assay value, water content etc.
 The working standards should be checked before use for testing to
ensure that it has not deteriorated or decomposed during storage.
 All the above said materials should be stored at appropriate storage
conditions.
 The lab should have proper microbial stock cultures & SOP should be
prepared for Sub cultures, preservation, storage (NMT 5 passages).
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Internal Quality System Audits
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Laboratory Building & surroundings
Premises (including Animal House)
Personnel
Equipments
Chemicals & Reagents
Good House keeping and safety
Maintenance, calibration & validation of equipments
Reference materials
Microbial cultures
Aseptic areas (microbiology and sterility if applicable)
Quality system
Storage of starting materials and finished products
Documentation
Sanitation and Hygiene
SOP`s
Protocols & Specifications Archive
Raw data,
Storage & Archival
Corrective actions on previous reports
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Protocols, Raw Data & Specifications Archive
 Specification: A list of detailed requirements (acceptance criteria for the
prescribed test procedures) with which the substance or pharmaceutical
product has to conform to ensure suitable quality.
 Protocol: Protocol is the documentation of all necessary specifications,
calibrations, operating ranges, etc. Environmental factors such as
temperature, humidity, barometric pressure, and other factors can often
have effects on results.
 Raw data :refers to the laboratory work sheet, note books or analysis
sheet, records, memorandum, notes or extract copies thereof that may
be the results of general observations and other activities of raw data
includes written notes, photographs, software, drawings, spectral
charts, computer print outs, dictated observations or recorded data
from automated equipments, calibration records, record on receipt of
animals, results of environmental monitoring etc. if any change in the
raw data a single line shall strike through the data with signature and
date.
 The data integrity and security shall be maintained and not allowed for
unauthorized person.
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Storage & Archival
 Residual sample shall be retained under proper storage
condition for period of one year after the final report.
 The lab should have well defined plan procedure for the
identification, collection, indexing, retrieval, storage,
maintenance and disposal of all quality documents.
 The lab should have well archive for storage of documents to
prevent modification, damage or deterioration or loss.
 The original documents should be stored in secured area with
restricted entry.
 Paper documents should not be stored under high humidity.
 A photocopy of the thermal paper shall be retained.
 The documents should be retained as per the D & C Rules.
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Advantage India
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Proactive Government Policy
Fair & Efficient Judiciary
Established Pharma/biotech industry
Availability of Pool of Trained Man Power
Entrepreneur skills
Communication in English
Strength in IT, BT and PT
Potential Market
Requisite infrastructure
Communication System
Transport System
Well-established Hospitals in the Government and Private
Sector facilitating clinical research for Biotech products
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Challenges
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Logistics
Communication skills
Training
Cultural Integration with Partners
Lack of interaction between academia,
Regulatory affairs
 Lack of application of knowledge
 Lack of Leadership
industry
&
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Ten Commandments of Success
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Speak to people: (There is nothing as nice as a cheerful
greeting)
Smile: (It takes 72 muscles to frown only 14 muscles to smile)
Call people by name: (Everyone is pleased when you
remember their name)
Be friendly and helpful: (And others will respond in like
manner)
Speak and Act: (As if everything you do were a genuine
pleasure)
Be genuinely: (Interested in people)
Be generous: (We praise, cautious with criticism)
Be considerate: (With the feeling of others it will be
appreciated)
Be thoughtful: (Of the opinions of others, there are three sides
to any controversy, yours, the other persons and the right one)
Be willing: (To give service, what counts most in life is what
we do for others)
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What is Life?
Life is like a game & juggling some five balls in the air.
They are
Work, Family, Health, Friends & Spirit
You will soon understand that work is a rubber ball. If
you drop it, it will bounce back but the other four ballsFamily, Health, Friends & Spirit are made up of glass. If
you drop one of this they will be irrevocably scuffed,
damaged, marked, nicked or even crushed. They will
never be the same. You must understand that and strive
for it.
Work efficiently during office hours and leave on time.
Give the required time to your family, friends & have
proper rest.
“Value has a value only if its value is valued”
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Thank You