#2 ISPE Schedule L1

“Schedule L1”GLPs in Drugs &

Cosmetics Rules

Kapil Bhargava

Dy. Drugs Controller (I) retired

Introduction

For GLPs a newly introduced Schedule in

Drugs and Cosmetics Rules

It is applicable since 01.11.2010

Till this introduction, GLPs were not

addressed as a legal requirement (Except

few of the conditions were mentioned for

PTLs in part XV (A) of D & C Rules)

• WHO – GLP is in draft form

• Another WHO draft only on

microbiology labs

• Both above are “guidelines” and not

legal requirement

• Not conforming to GLP may attract

administrative or legal penalty

Introduction

Presentation shall cover

• Salient features of this schedule

• The different provisions those have

been added now

• Difficult to understand requirements

– Their logic

• Clarifications required by / from

regulatory bodies for implementation

of requirements

• Technical manager or Quality Manager

– Current mfg. lic. mention “expert

technical staff for testing”

– Responsible for “all technical activities”

– Implementation of documented quality

systems

– Responsible for technical audit of the

laboratory for GLP compliance by an

expert appointed by the top-management

Personnel

2. Premises

– (a) (i) the laboratories shall be designed,

constructed and maintained so as to

prevent entry of insects and rodents

besides cross contamination

besides cross contamination – Cross contamination in the laboratory is to be avoided

Two different samples cannot be handled by an

analyst and so on..

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HVAC

• (iv) air ventilation system shall ensure

dust free environment

– Installation of HVAC is essential now

– Design of the lab need modification and

the project in-charge or site engineer

must very clearly understand pressure

balancing (more so when fume hood is in

operation)

– Humidity control is also necessary

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Premises / Work Area

• (d) Tabletops shall be constructed with

acid, alkali, and solvent resistant

material and shall be smooth and free

from crevices as far as possible

– In case this is not existing, the table

tops are to be replaced

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Premises

• e) All bio-medical laboratory waste

shall be destroyed as per the

provisions of the Bio-Medical waste

(Management and Handling) Rules,

1996.

Premises

Sterility Test Area

• (g) The air circulation is maintained in

the area where sterility test is carried

out as per Schedule „M‟

– Schedule M does not prescribe air

circulation for testing laboratory,

requirement is for mfg. areas

• (h) Bio-burden shall be routinely

maintained in the controlled and

uncontrolled area. (e.g. air locks)

– It is not good to “maintain” bio-burden

– It is to be controlled

Premises

Animal House:-

• (i) Animal House shall have the

approval of the Committee for the

Purpose of Control and Supervision on

Experiments on Animals (CPCSEA).

Animal House

• (ii) Designed in such a way that there is

an arrangement to quarantine the new

animals procured or purchased and

have a provision for clean corridor and

dirty corridor

– Clean and Dirty corridor -- Very difficult

provision for already existing animal

houses particularly those attached to

small size mfg. units

Personnel

• (c) Head of the laboratory must be of

high professional standing with

experience in drug analysis and

laboratory managements who is

responsible for…. :

– high professional standing!!

Personnel

• (iv) taking final responsibilities for

recommending any regulatory action

in the event of non-compliance of

tested samples

– Head of the laboratory is now expected to

recommend to management the

regulatory action to be taken for non

compliances !!

Equipment

• (f) A progress register for non-

functional equipments and action for

procurement of spares and

accessories, monitoring thereof, shall

be maintained.

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Equipment

• (g) A Standard Operating Procedure

for preventive maintenance of machine

or equipment or apparatus shall be

prepared by the laboratory

– A matrix and compliance to this schedule

– Demonstration to this compliance

Equipment

• (h) Other equipment such as burettes,

pipettes, volumetric flasks, weight

boxes, thermometers, etc., shall be

thoroughly checked for calibration

before acceptance for use

– Laboratory Glassware are termed as

“equipment”

– It is to be decided if supplier‟s certificate

will be accepted or not

Equipment

• (i) Maintenance procedure in the form

of Standard Operating Procedures

must be prepared and regular

servicing must be performed by the

maintenance engineer or specialist

– Requirement of a maintenance engineer is

now essential

Equipment

• (l) Autoclaves must meet the

requirements described for

operations, safety and validation

procedures, and the validation carried

out by the laboratory shall be recorded

Reagents

(d) Containers of stock solutions and

of standard shall bear the following

details-(i)

(ii)

(iii) “use before date” depending upon

the stability of the solution; and

(iv) standardization records - It is very

difficult to mention standardization

records on stock solution containers !

Good house keeping and

safety

• (iv) the laboratories shall have

adequate first aid kit and fire fighting

equipments located at the right places

and the staff must be familiar and

trained with the use of fire fighting

equipment including fire extinguishers,

fire blankets and gas masks.

– fire blankets and gas masks are essential

now

Reference Materials

• 8 (a) Reference materials are

necessary for the testing and, or

calibration, validation or verification of

a sample or of equipment, instruments

or other devices and all such materials

shall be traceable to agency

authorized by Government of India or

any other International body

– Difficult to comply!

RS/WRS & Secondary

Std.

• Standard Operating Procedure (SOP)

for the maintenance of reference standards and evaluation of Working and Secondary standards…

– Ref. Subs. (Official)

– Ref. Subs.

– Secondary Ref. Substances

– Working Standards

Working Standards

• (b) The laboratory shall prepare

working standard by comparing with

the reference standards and shall be routinely checked for their purity by

selecting parameters such as identity,

loss on drying or on water, impurity

and assay, etc.

– Difficult to comply!

Reference Material

• (c) Wherever, any new reference

material is received by the laboratory,

a code number shall be assigned and

this code number shall be quoted on

the laboratory note book and analytical

work sheet.

• The working standard shall also be

provided with identification code.

– purpose of this requirement is unclear

Working Standards • (e) All working standards shall be

checked at appropriate intervals or

before use to ensure that it has not

deteriorated or decomposed during

storage.

– Checking deterioration or decomposition

frequently or prior to use is very difficult

and also time consuming . It may not serve

the intended purpose .

– This may be OK for PTLs or Government

Laboratories

Microbiology Cultures

• (b) if the cultures have become non-

viable or mutant, proper procedure

shall be followed to destroy these

cultures by autoclaving under an

authorized personnel for biological

testing. Preferably not more than five passages may be prepared.

– This is to be more scientific – Checking

culture purity is to be emphasised

• (d) The laboratories shall perform

standard biochemical tests on the sub-

culture as given in literature to ensure

their viability.

– Biochemical tests are time consuming and

rather tough to be performed on each

subculture

Microbiology Cultures

• Practically it is not feasible to perform the

biochemical tests prior to use of every culture

• Alternatively whenever a new vial of Working Seed

is used to prepare fresh slants for routine use, the

purity and characteristics of the microbial culture

shall be confirmed by microscopical and

biochemical examination

• These slants thereafter can be used for routine

tests for a period of 1 month restricting the passage

up-to not more than five

Microbiology Culture

Microbiology Work

• (c) All activities be carried out in a

aseptic area by authorized person.

– Now aseptic area is needed for all

microbiological work – In existing

laboratories Aseptic area is difficult to

create (or upgrade)

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Microbiology Work

• (d) The laboratories shall perform

standard biochemical tests on the sub-

culture as given in literature to ensure

their viability

– Each sub culturing all biochemical tests

are expected to be carried out

– Viability can be tested by other means too

– This provision is more suited for

preparative work

Quality system

• The quality system shall be designed

to ensure the following objectives:-

– (a) the measurements and calibrations

shall fully conform to the compendial

requirements and methods demonstrably

based on validation protocols are followed

• Method Validation for all the analytical

methods is compulsory now!!

• No references in IP or Drug Rules are

available

Internal quality system

audits

• (a) Internal audits are done…. to comply with requirements of regulatory authorities.– Some Check-list from Govt. is needed

Internal audits shall be carried out by trained and qualified personnel who are independent of the activity to be audited

In smaller labs this too is difficult for compliance

SOPs for:

(i) sample handling and accountability;(ii) receipt identification, storage mixing and method sampling of the test and control articles;(iii) record keeping, reporting, storage and retrieval of data;(iv) coding of different studies, handling of data including use of computerized data system;

SOPs for:

(v) operation of technical audit personnel in performing and reporting audits, inspections and final report reviews;(vi) routine inspection of cleaning, maintenance, testing, calibration and standardization of instruments;(vii) action to be taken in respect of equipments failure;(viii) analytical data methods;(ix) the raw data;(x) data handling and storage retrieval

SOPs for:

(xi) (xii)(xiii)(xiv)(xv) maintenance of sterility room (i.e. constant maintenance and monitoring of Aseptic condition of sterility room)(xvi)(xvii)(xviii) monitoring of testing of samples – I have not understood this SOP(xix) methods of retention of unexpended samples, their location, maintenance and disposal – easy to write SOP but difficult to comply

(xx) document control

SOPs for:

(xxi) redressal of technical

complaints;

(xxii) housing-keeping

(xiii) corrective and preventive action;

(xxiv) working procedure (test

methods);

(xxv) calibration Manual; and

(xxvi) training manual.

Protocols Archives

• (b) All updates and corrections must

be noted in the master volumes of

Pharmacopoeias to prevent the use of

obsolete sections; supplement and

addendum shall also be made

available in the laboratory.

• (c) The specification archive shall

contain the following:-

Protocols Archives

(i)(ii) a file on patent and proprietary medicines (non- pharmacopoeial) test methods to specifications prepared and validated by the manufacturer or by the laboratory itself.

The test methods shall be submitted to the concerned Drugs Control Authority.

The validated test methods developed by the manufacturer or the laboratory shall stand to the requirements of compendial parameters in regards to its precision, accuracy, reproducibility, specificity, linearity, and ruggedness etc.

Storage and archival

• (a) The residual sample shall be

retained in proper storage condition

for a period of one year after the finial

report.


• (b) The laboratory must establish and

maintain procedures for the

identification collection, indexing,

retrieval, storage, maintenance, and

disposal of all quality documents.


• c. The archive shall provide a suitable

environment that will prevent

modification, damage, or deterioration

and/ or loss


• (e) Paper documents shall not be kept

for long periods under high humidity

and raw data in the form to tape and

discs are to be preserved with care

• (f) In case of storage of only optical

disc, the life of disc shall be longer

than the storage time


• (g) Raw data on thermal paper might

fade away with time; therefore, a

photocopy of the thermal paper shall

also be retained in the archive.

• (h) Time for which records are

retained shall be prescribed in the

documents.”

Summarizing

– Provisions in Schedule L1 are legal

requirement and are to be complied with

strictly

– Clarifications for provisions which are

rather ambiguous may be sought for from

regulatory authorities

– Few actions for compliance are also

expected from regulatory authorities.

My references were•Schedule L1, Schedule M, WHO TRS and other WHO documentsAcknowledgements •Support from Mr. R Raghunandanan, my colleagues, ex colleagues and professional in the industry

26th Feb. 11 [email protected]

26th Feb. 11 [email protected]

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#2 ISPE Schedule L1