Analytical

Quality Control for Raw Materials used in drugs. Committee,

Production of Plant -based

~"'iss. S. Satakopan*, Member, Ayurv~dic Pharmacopoeia Ministry of H & FW., Govt. of I'fldia.

am happy ta have this opportunity ~o address this group of scientists from India 3nd its neighbours understand medium related and thank the organizers for their invitation to me. to help the small and knowledge I also drug learn and skills that the I

that the present training course is an endeavour in India and other countries control from the for drugs small of natural and medium acquire origin. scale

enterprises to quality

pC"1rticipants are companies,

manufacturing Most

as well as from the enforcem~rit of the Eastem hemisphere

agencies

of these countries.

of the collntries

have a repository

of traditional drugs No doubt

of natura! origin, built on a heritage they would '!ke to avail themselves course, so that they could organize

of indigenous

medical systems.

of the infon11ation gathered quality control facilities

at this training back home and

enable th~ir people obtain safe and effective remedies at reasonable cost, under their law~. Having worked with raw materials and finished products of Ayurvedic at their

dru')s while in service with the Gujarat State Drugs Control Administration Laooratory sharing drugs at Vadodara

for about twenty five years, I believe I can contributE by on this very challenging systems. aspect of quality control for the would be quite

my experience of the indigenous

I know that the participants

familiar with the definitions and significance

of the various terms related to quality

control, but nonetheless, I should lik3 to make myself clear by explaining a few of these; not only because the:' deal with the basic principles of regulatory analysis, and therefore must be correctly understood, but also because of their frequent misuse by mc..ny working in the field. Tr.e terms 'quality', 'specifications', 'standards', and 'stardardisation'
-

are

often used in connection with a Pharmacopoeia, and must be understood in their

.Pres..~ntAddress

: No.7/4, Seventh

Street, Nanganallur,

<:;hennai -600

061,lndia.

"I

exact SAnse. By ',g!;!.!j!y'is meant the essential nature of a thing, (a drug) and the tGtality C'f its attributes and properties which bear upon its fitness for its intended use. We refer to pharmacopoeial or compendial 'Specifications' quality to indicate the fitness of comprise a set of selected and associated

an article. to be used as a drug. desc~iptive terms (parameters) test methoas, performance required covering

with appropriate

set of 'standards' 'Standards'

the quality of a drug.

indicate a level of so that the period of its

or a scale by which pre-set valLes can be measured, within a reasonable

quality of a drug may be assessed 'Standardisation'

existencG in the market.

refers to a process

resulting from a

consenSIJS based on scientific findings, obtained maY refer to a manufacturing equipment, purpose. operational process,

by parties most affected by it. It of test, calibration required of an fc..r a

or. a method

procedures

or any

set of conditions

It deals with formulating

and applying rules for an orderly approach to a of, all concemed. It is

specific activity for the benefit of, and with the cooperation different from, and should not be c)nfused with, 'standards'.

~harmacoP()eia -Status
The Pharmacopoeia reached

.And Functions:
is a public document resulting form a consensus of drugs,

by the parties most affected

by it -that

is, the manufacturer

the Government,

and the body vested with po~/ers to prepare a Pharmacopoeia, under the Government constituted or independent of of

which i~ a Committee or a Commission it. The Ayurvedic India has been Pharmacopoeia responsible

Committee

by the Government

for the preparation

of the Formularies

and the

Pharmaco,:>oeiae published till ,lOW. Most drugs manufactured the recommendations Committee. Formulations in a country obtain pharmacopoeial status on in the

of the medical profession

which is we:11 represented

In India, a team of eminent Vaidyas and Hakims selected medicinal that were ~useful. most commonly prescribed. and the lonqest

in existence to be included in the first Ayurvedic, The single drugs of natural origin used as

Unani and Siddha Formularies. raw materials in the selected

formulatiol1s were also identified and listed under their scientific names.

3 Ayurvedic Pharmacopoeia prescribes standards for the single drugs of botanical,

ar'limal and mineral along with associated the basis of data origin used by the manufacturers method~ in its monographs. from collaborative as their raw materials, are assigned on

Standards work

collected

and existing

published

informatio~.

Standards

are necessary

so that a consistent

level of performance should be realistic, capabilities. They

may be expected ration'3l, attainable

of drugs complying with it. Such standards by an industry with differing technological

are safety standards,

and need not be more strirlgent than required for a drug Standards for marketed drugs or raw materials are but thl3Y should be good enough to of spurious or adulterated Any drug falling below

under given circumstances.

nG)t meant to certify 'excellence' guaranteG

in quality,

safety for the consumer

from the ill-effects

drugs a.ld help him recover pharmacopoeial Although compliance standards

from his impaired health.

should be declared as 'unfit' for use. is obliged to ensure that his products obtain

a manufacturer

with the Pharmacopoeia,

he should

not be satisfied with products In other words, total for

that just toe the line of quality specified Pharmacopoeial quality assurance standards

in a Pharmacopoeia.

are not the manufacturer

j' means of achieving for the manufacturer

nor do they serve as a threshold

'batch re:lease'. An ethical Pharmaceutical manufacturer of Ayurvedic, Siddha or

Unani drugs must ensure that both his raw materials and finished drugs are of much higher quality than that required by the pharmacopoeia. would er:sure that any single container by regulatory with prescribed choose officials within its shelf-life requirements. of testing, although In fact, this a!:Jne

of his product, picked up from anywhere period and sent for analysis complies however has the freedom to

Tile manufacturer and not necessarily in cases of dispute

his methods

follow the methods given in or adverse reports on his

the Pharmacopoeia, samples,

he is called upon to use the official method and establish compliance. of a country is the backbone sold, distributed of regulatory control of or imported into that alive and

Ttle Pharmacopoeia the quality country.An

of the drugs manufactured, efficient regulatory

system will keep the Pharmacopoeia

dynamic. A purposeful Pharmacopoeia is a valuable and able instrument in the hands of the enforcement agency. Thus they are complementary to each other.
The unattai1able characteristics detectio,l constituted and uniqueness high levels of pharmacopoeial of quality for a standards drug, but lies, not in dictating in providing to enable incorrectly task

rather

that would be both comprehensive rejection that of may non-genuine,

and discriminato!y, degraded is quite or

impure, This

drugs

be in circulation.

a difficult

considerir 19 the large number have in t1e Ayurvedic

of single drugs given

pharmacopoeial

status. We

Pharmacopoeia,

over six hundred single drugs, of which

some fif;y are of animal, and about the same number, of mineral origin. The fivehundreC;-odd fJlant based drugs, may be eIther derived from individual parts of a plant, or may be used as whole plants. When a large nur,lber of crude drugs, SE-Y,roots, features are derived from different plants one has to look for very specific so that the monograph differentiation of one may contain other discriminating similar roots.

In root anatomy to allow

characteristics Oth~rwise,

root from

the monograph

will not fulfill its function

of E;stablishing genuineness and negligence or

of that root. This is the toughest part of work for a monograph, lack of skill here would cost the effectiveness is the watch-word. seemingly This makes the monograph anatomical details,

of a monograph dearly. 'Specificity' elaborate and cumbersome, with the

illessential

but it is worth the pains, because contribute

macroscopical

and microscopical

details for identification

the major

part of a manograph. ~he second important are confined quality requirement is for 'purity'. limits, Physical and

o..ganic impurities tolerance

to reasonably

minimum

by prescribing

limits for 'foreign matter'. Traditionally,

'foreign matter' means anything Even other parts of the of

other than that defined

as the drug in its monograph.

same plant from which the drug is derived,

but not included in the definition

that drug, will be treated as foreign matter. Thus if a seed is defined as the drug under definition, the fruit parts would have to be eliminated. The limits for foreign without any further

matter should be fixed only for those drugs that are used treatment but enter the formulation

as they are. For ~hose drugs from which

extracts

or oils are prepared

on a large scale in the manufacturers'

prem:ses,

limits for' foreign matter have no meaning, and good house keeping is enough to keep down contamination. On the other hand, no toleran('~ should be allowed for insect debris, or other obnoxious substances. impurities like siJil, microbial contamination,

such foreign matter as filth, fungus, Freedom pesticide residues from inorganic

etc., are a necessary

part of monographs

for raw materials,

and well accepted

tests are in existence for these. of a crude drug, expressed in terms of its active ingredient,

T;,e 'strength'

is an indication of its efficacy as a therapeutic agent, and is given by an assay for an active ingredient. their therapeutic For crude drugs of I)ur traditional systems, establishment of

value is on the basis <-f their long standing

use for a disease,

and not on the basis of 'clinical trials' ~s it is understood drugs. known Where the active ingredient and where responsible the

for western sYllthetic activity is

for the therapeutic

and measurable,

structure-activity

relationship

is well

established,

an assay by conventional is lacking.

methods is prescribed,

but for most drugs values, total

this information

In such a situation, sugars,

certain extractive

volatile matter, or oil, tannins, Several modern methods

proteins etc., may be used as indicators. HPTLC etc are also in vogue, but these

like TLC,

serve I nore often as identification

tests than as an assay

Mineralr.,

Metals and Animal

druQs:

A'Jout a hundred single drugs are derived from the crust of the earth and from wild or domesticated these animals. Unli~e plant drugs, which are huge in

number, literature,

are only a few.

Better recorded

data is available

in scientific

making the task of building monograph the same quality specifications

much easier. For the minerals and

and metals,

used for their identification

'1ssays in the geological sciences the animal drugs also recorded relevant details for preparing

and metallurgical data are sufficient,

chemistry are adaptablE"). For and it is possible to select

a monograph.

One area of concem would be the and listed as such, under

USE.of certain parts of animals

that are endangered,

world protection.

In such cases a radical rethinking

is necessary,

even to the

exterlt of putting an end to their use.

~g

rl1ethods for Raw Materials:

Tests should accompany each specification the specification, in a monograph. or they These may, in an

if short,

be

stated

along

with

may be

accompanying understand

annexure.

What is more important are the principles one need to test methods for the pharmacopoeial drugs,

for suggesting

1. Tests should be rugged. radically affected environment, climate,

That is, the method of testing should not be like laboratory seeson or

by a variety ~f normal te~ t conditions approach, This instrument may sound

analyst's

behaviour,

or age

of reagent.

a tall order,

but on

examination

it will be seen that most gravirl1etric tests, and indeed, in several pharmacopoeiae are

may tests that are now in existence sufficiently rugged. 2. Tests should be reproducible products. execution 3. Specificity They should

and cover a wide -:-ange of manufactured require much sophistication in

not normally

or highly sensitive and costly instrumentation. is more important for plant based drugs or raw materials, The tendency in analysis of modern synthetic drugs is more and more sensitive analysis and detect even

than sensitivity. to move towards nanogram

quantities

of an active ingredient that are highly potent and in a dosage form. Since this is not the gram-quantities are more the of a raw

used in very small quantities situation

in plant based drugs, where is not a vital issue. drugs used

rule, sensitivity number

But specificity is, because formulations. In

of single

in compound

materials, also specificity, 4. The test methods

and not sensitivity, is the issue. be applicable to a laboratory reference

should

preparation. substance different

It must be pointed for crude drug

out here that the use of reference or for formulations has a of

examination

purpose

and it is not similar to their use in the analysis

rnodem drugs. In the latter, the reference substance is balanced against a drug that is under assa~' for comQarison of its strength or ~y results by instrumental methods. But in the tests for plant based

drugs, it is for ~alidting the method used.5. The monograph should not be loaded with too many tests, specially if they would not be discriminatory.

A Modus-Operandi:
The above passages aspects of analjtical have, although briefly, touched control, and highlighted upon the important the role of the

quality

pharmacopoeia ttle activities work.

in achieving

this aim. The accompanying

flow chart will illustrate

that have to be co-ordinated

to gathe;r data for pharmacopoeial for their products, by

This may be put into operation agencies

by manufacturers

enforcement by researcll

of the Government

in their regl.Jlatory operations,

or even

institutes interested in plant based drugs. They may need to adapt or

alter slightly to suit individual capabilities.

Participants The Crude

in Analytical DruQ Market:

Quality Control:

Their Attitudes

and Approaches:

Almost all eastern countries of home-made

have a thriving crude remf3dies and cheaply as and

drug market because manufactured

of the popularity

indigenous

or folk medicines.

Crude drugs are collected cultivation

when available in Nature from

the wi:d. Although

of elite strains and are available, these of crude drugs that

hybrids, tissue culture methods and many more technologies are restricted to a few well-known species, but hundreds

enter the market are from the wild. Nor is the sale of crude drug by local dealers under any jicensing system. The onus is upon the buyer to guard The question of licensing against

spurious

or sub-standal

j raw materials.

system for

local dealers has been mooted before, but given up (rightly so, in the opinion of this speaker) as the odds were too many. It is also realised that once the quality of raw mater:als and that of drug products manufactured from them are covered

by statutory requirements through a pharmacopoeia, the unwanted, spurious,

spoilt, or carelessly collected and stored crude drugs will be weeded out of the market i1 the natural process of discriminatory purchase of raw materials by the users. Additionally, an educational appro, ch by the govemment, by bringing out an authentic MCiteria Medica listing approved natural resources in the country will greatly enhance quality consciousness in the dealers. The Jndiaenous Pharmaceutical manufacturers, small, medium Industry: A great responsibility lies with the towards quality

or big. Their contribution

standards for raw materials and finished products should be very much more than now. But no initiative has emanated from them on a national scale. It may be pointed out that i:1 the case of the pharmacopoeial drugs of the western or modem medicine, such as those inclujed in the Indian Pharmacopoeia, the

standards for both raw materials and finished products are almost wholly the work of the pharmaceutical industry. Only corroborative work is under taken by the Pharrr,3copoeia Committee, before finalising the standards. Similarly, the indigenous pharmaceutical provide public standards pharma~opoeia. manufacturers also must take it upon themselves to for their produ~ts and help in building national that they are obliged to prepare 'in-house'

Considering

standard for their products, (which are at a higher level of performance than that pr;scribed in a pharmacopoeia) no srecial effort in India are on their part is called for. Much is also

Nlanufacturers

subject to GMP regulations.

expected of them with regard to the SOPs they record for their products. For example, the Ayurvedic Formulary comprising of formulations which are fixed combinations, has laid down coMplete instructions for their preparation by the Vaidya or Hakim. But unlike ear1ibr times, such preparations are not now in the hands of the practising :Iinician or in his small pharmacy. necessary It is therefore

that these operating procedures are re-'Nritten with an exactness in modem quality control requirements. Consistency of quality in a

keeping willI

large scale manufacture would only then become feasible. Indigenous drug manufac~urers should emulate the discipline that characterizes the modern pharmaceutical industry.

The EnforcinQ a government

AQencv: department

Every country oversees the health of its people through meant for the purpose and th s generally has a nodal

agency for taking care of drug quality, even if only imported for the time b3ing. While the government to perform, testing within. departments have, to a large extent, administrative providing a well-equipped whether imported duties for

they should also envisage

laboratory

raw materials

and drug products,

or manufactured any

Only then they may be said to have the capacity for implementing Inspection of manufacturing facilities

quality control programme. samples monitoring formulations, for checking by the

and collecting

their quality at their testing laboratory government. With respect to

is a routine part of drugs and of

indigenous

the inspectors

may have to go a bit further than routine sampling It is necessary to understand

'end products' for official analysis.

that 'end product'

analysis, which works well enough to achieve its purpose for modem drugs, will not be so profitable with natural products. ' End product' analysis of a modem synthetic drug reveals a lot about the histlry of the drug -the raw materials

used, the process followed, the impurities, the additives etc., However, many indigenous drugs or fon11ulations (though, thankfully, not all) are not simple combinqtions of one or two substances. A number of ingredients are combined, and the process of manufacturing is also quite complicated. There are no analytical methods that can establish proof of 'batch quality' from the results of analysis from a single container picked up by an inspector. Analytical parameters .9.@ available, and quality ~ be estimated, but only to a certain extent. In such a

situation, apart from one container of the end product, more evidence should be available to the analyst, so that he can come to a reasonable conclusion about
the sample. purposeful information samples What ill~pection is needed therefore is for the Inspector to combine a

with judicious

sampling

that would

help give as much

c.S the analyst requires.

One way would be for the Inspector to send

of the raw materials used in an end pruduct, as 'satellites' to the sample

of that end product. This would greatly help the analyst not only plan his strategy for devising analytical methods suitable for that product, blJt also help him

validate his methods of test.

10

The InspectQr should also resort to a heavy sampling programme materials from the This manufacturers' stock, or while in the

of raw of

process

manufacturirlG.

would throw light on the quality of raw materials purchased which in turn, would reflect the quality of the final product.

by the manuff1cturer, Fortunately,

raw material analysis is not different from that for mcdem drugs and

analytical literature abounds with information. It should laboratory be mandatory for both the manufacturer and the government is

to hold authentic

reference standards.

In addition, the manufacturer

also e.xpec;ted to keep back-log samples that would help in rechecks. In India, management With the great strides have been made by the Govemment in the

of a quality control system for Ayurvedic, of several parts of the

Siddhe and Unani drugs. Pharmacopoeia it appears that a

publication

Ayurvedic underway,

for single drugs, and one for the finished long -time dream is taking shape.

products

you,

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Thank

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