Overview of GMP for the manufacturing of herbal

preparations and herbal medicinal products

Götz Harnischfeger

ICS-UNIDO Training course on: Development, quality assurance and regulatora aspects

ofherbal medicinal products; Panama City, Panama, 21. -25. November 2005
When manufacturing medicinal products in general and herbal medicinal products in

particularwith this GMP (good manufacturing procedure) outline in mind, the patient can be

assured of recieving a product of reliable strength unchanged from batch to batch with

continuously high quality and efficacy. Under this acronym GMP, defined as

that part of quality assurance which ensures that products are consistently produced and

controlled to the quality standards appropriate to their intended use and as required by the

marketing authorisation or product specification

guidelines adressing the following aspects were deviced (fig. 1).

Originally developed on a national and/or continental level, the GMP documents have been

harmonized and formally effected by the WHO to provide a suitable tool for certification,

government control and licensing in the international trade (1,2). The guidelines encompass

practically proven recommendations and procedures for controlling the manufacture of all

types of pharmaceuticals and include precautions to prevent adulteration and contamination.

The basic requirements around which the GMP guidelines are formulated are depicted in the

table below.

These general principles need, however, to be adopted to special segments of the

pharmaceutical industry, in this case to the processing of herbal starting material and for the

adjoining manufacture of herbal medicinal products. The line separating these two is

sometimes difficult to draw, since intermediates in one case might, at the same time, in

another be finished pharmaceutical products. Examples are the herbal tea or the simple plant

tincture. GMP restricts itself not only to the manufacturing steps themselves but includes

starting materials, intermediates and the final product as well. The same general principles are

valid throughout.
To understand the general concept of GMP from a praxis-orientated point of view, it is

helpful to focus primarily on systems and sequences of the manufacturing steps with their

critical areas, assuming an inspectors way of assessing a process. Cross reference can then be

made to the various sections of the WHO-GMP guidelines (2,3).

The evaluation for quality and safety levels aimed at by such assessment covers the

following:

- the materials (starting material, storage and packing material, excipients

etc.)

- the processes themselves

- the herbal product (intermediate and final) and ist compliance with the

necessary quality characteristics

- the technical and non-technical environment with regard to possible

risks

of adulteration and contamination

- the personnel; it’s state of training and willingness for responsibility

- the effectiveness of an independently run quality assurance system

- the documentation and archivation system

Implementing the GMP system might look difficult, since on first sight it appears that

enormous investments have to be made deterring from action. However, the monetary outlay

can be reduced considerably, if the approach to GMP starts with those aspects which cost

little or no money but require only some logic rethinking and physical effort. Starting with

these, it is amazing, how far one gets along on the path of GMP compliance.
General evaluation

In a first step a written check-list is prepared in order to identify and focus on critical aspects

helpful for analysing the final (marketed) product. The list might be organised in the

following way:

- the therapeutic use of the product, the primary and secondary active

components, if known

- specifics of the galenical preparation and methods to achieve it

- content of active or guidance components aimed at in standardisation

- packing material to insure stability and effectiveness under prevailing

environmental conditions

- labeling requirements

This frame of reference establishes an outline for a more detailed analysis. Thus with high

probability all the necessary parameters important for pharmaceutical quality are defined and

covered.

As mentioned, the general set of rules had to be annexed to take care of specific problems in

the manufacture of herbal medicinal products, radio-chemicals, veterinary products, sterile

medicinal products etc. National authorities have issued additional interpretations of

individual rules in order to clarify them or to prevent misinterpretations. Unfortunately, the

latter has formalised the use of GMP to such an extend, that the basic issue is hardly

recognisable any more.

It has to be recognised, that herbal medicinal products have no special status in GMP. Most

of the rules for the various aspects shown before apply to them as well. There are, however,

some peculiarities in the complex of production and quality control. A general outline of these

aspects is given in a supplemental guideline issued by the WHO.

Basic requirements

The basic requirements for GMP are outlined in figure 2. Some comments in the light of my

experience with the manufacturing of herbal medicinal products might be allowed.

It is a necessity, that the manufacturing process is invariable, giving fixed target parameters

for every step and relying on written SOP’s.

Since the quality of every batch of raw material (plant drugs) varies, an equalizing step

according to s specification should be applied at the earliest possible step.

It has an advantage, if the product batch is quarantained after every step in its manufacture

and resumption of processing should only continue, if an analysis at the control laboratory has

resulted in ”complies with the specification”.

Evaluation: starting material

The main focus of a manufacturer has to rest on an exactly specified quality (acceptance

quality) of the herbal starting material, i.e. its identity, purity, content of active substance or

marker, micro-bioburden, specified technical parameters etc., which has to belaid out in a

pharmacopoiea type monograph. Since by its very nature the quality of every batch of herbal

starting material varies within a certain range, an equalizing step should be applied and

looked for at the earliest possible occasion. The process and target specification should be

available in writing. Documentation for every lot is necessary.

A critical variable is the bioburden of the herbal material. A validated method of reduction

should exist, whose results are closely monitored at regular intervals.

The acceptance quality of excipients and solvents should be similarly specified in writing.

Especially water should be checked regularly for bioburden.

Next to these basic documents, certificates of origin, collecting or growing records and on site

processing protocols should be available for every batch recieved (4,5). This has been dealt

with previously.

Periodic audits of suppliers by a responsible representative of the manufacturer are increasing

the compliance with the required quality. To underscore the importance of quality control and

adequate acceptance criteria for herbal drugs, it is worthwhile to know, that a large percentage

of FDA warning letters adresses shortcomings in this particular area.

Another point of importance is the storage of the various materials. For this purpose an annex

to the WHO-GMP (4) and also a special GMP, Good Storage Practice (7) has been enacted.

The basics are given in figure 3.

These special requirements for herbal products adress mostly concerns with dust as carrier of

microbial contamination.

However, most of the microbes are no hazard to human health. Testing for guiding types of

pathogens (E. coli, Pseudomonas, Staphylococcus) suffices. In addition, in ethanolic extracts

>23% their quantity will decrease by several orders of magnitude. However, if water is used

as extraction solvent, microbes on the herbal starting material certainly constitute a problem.

In this case, dust should be kept at a minimum. In general, it is advisable to have dust

eliminating ventilation installed at all those places where it is generated.

Evaluation: processing

The GMP for ”Active Pharmaceutical Ingredients” (APIs) of EMEA (6) defines the border

line separating the processes where the strict rules of GMP strictly apply from those where

they are only advisable. In herbal medicinal products, GMP starts after the initial extraction

step (fig.4 ).
Process evaluation

The critical step: a ”critical” step is a matter of definition. It usually is reserved for process

concerned with the safety of the finished product, e.g. pyrogenicity and purity in sterile

products, where special sets of parameters have to be kept. In the normal manufacturing of

phytomedicines, e.g. making of tinctures and extracts, the conditions can, as a rule, be

classified as uncritical

The processes: The best way to proceed with process evaluation according to GMP is by

using a flow diagram, which breaks down the respective manufacturing process into

individual, single steps (example given in fig. 5). Every single step has to be carefully

evaluated with regard to:

- adequacy of the technical process

- possibilities and avoidance of contamination/adulteration i.e. physical

prevention and adequate checking procedures

Such analysis provides the base for proper design of:

- written specifications describing the materials involved

- written procedure of machinery, processing and handling, SOPs

- protocol of manufacture with signatures, - at least two - , of responsible

persons in the documents

- validation of machinery and procedure, SOPs

- validated cleaning and maintenance procedures, SOPs

Simple processes like extraction according to pharmacopoieal monographs, as shown in fig.5,

do not need to be validated, as long as the DEV ratio and the nature of the solvent are fixed.

However, the many parameters influencing extraction (fig.6) have to be specified. This is also
valid for the related procedure of steam destillation, a technology used mostly for the

production of essential oils (fig.7). The figure gives a simple scheme together with the

pertinent variables to be controlled.

On the other hand, vaguely described processes, like the example of ”stir frying” of the

Pharm. Sin. Given in the following scheme have to be evaluated in more detail (fig.8).

The next step in process evaluation is a close look at all the manufacturing steps as a system,

i.e. as an integrated sum of individual manufacturing procedures. From this one can deduce:

- the critical steps and adequate control parameters

- necessity or deletion of specific in-process-controls

These considerations lead directly to the GMP requirement of validation.

Validation of manufacturing processes

It is expensive to perform all necessary monitoring procedures ona batch to batch base. In

order to cut down on the amount of analytical effort, the constant parts of manufacturing ( as

well as the afore mentioned routine analytical methods ) have to be validated. This is done

following a stringent procedure, to make sure that especially critical steps within a process are

properly controlled. The following figure (fig. 9 ) is an outline of the points which have to be

considered in process validation.

The entire processing has to be transparent, not only by SOPs and validation documents but

also by written lot to lot records.

Standard operating procedures

The formal makeup of an SOP will be treated in short. It is outlined in fig. 10.
It is advisable to formulate the SOP in a ”step by step” way, with room for remarks and

signatures of the operator. In this way, a copy of the SOP can be used as documented batch

protocol.

Operators should undergo training at least every quarter, especially in hygiene and safety

awareness (see below). Faulty operating of machinery should be discussed within the working

crew and remedies should be proposed. The supervisor present should write areport signed by

everybody present.

Evaluation: storage areas

A short compression of the GMP requirements was already summarised in fig 3.

Evaluation: plant environment

Main attention require the following areas (fig. 11 ):

- facilities: adequate design, easy maintenance, easy cleaning,

satisfactory hygiene standards

- sensible layout for economic flow through of products and goods

- isolation of problem areas (weighing station, mixing area etc.)

- condition and maintenance of general systems (electricity, water, air

cond.)

- security, restriction of entry

- plant safety, fire protection, explosion risks, hazard prevention

SOPs and advice for all these aspects have to be laid down in writing. Floor plans showing

the locations of power lines, water and sewer installations, air condition layout and locations

of hazard fighting equipment should be present. Important is an alarm plan and its regular

update.
In general, it is advisable, to have dust eliminating ventilation at all those places installed,

where it is generated.

Bioburden

Thee bioburden not only of starting material and final product but especially of the

environment is a critical variable. In this case, a validated method for reduction should exist,

whose results are closely monitored at regular intervals. Especially water should be checked.

The same should take place for the premises and equipment. The recommended values for

upper limits of bioburden are given in figures 12 - 14

Evaluation: personnel

Main aspects to focus on are:

- the work force: job description, level of responsibility, areas of

competence, safety training, health check up

- the responsible person: defined hierarchy, separation of responsibility

between production and QA, mediation in case of different decision

The expression ”qualified person” needs to be elaborated. In my experience, the senior level

in overall supervisory functions should be filled with registered pharmacists. An additional

qualification in pharmacognosy and technology as well as some industrial experience is an

advantage. Pharmacists have by training a better understanding of the technical aspects of

medicines, knowledge and a way of thinking which has to be acquired tediously by chemists

or engineers.

There are no special requirements in the area of training and personnel hygiene outside

general GMP in the phytopharmaceutical industry.

Evaluation: documentation

It is a generally required GMP procedure to document each and every step, be it

manufacturing directive, analysis method or training and maintenance action, on paper. This

requires in consequence proper archivation procedures with easy access for the individual

user. Some of these documents are:

- manufacturing permit

- contracts

- job descriptions

- training certificates

- SOPs

It is important to note, that no single production step should take place without a detailed

protocol signed by at least two responsible persons. Such batch records allow to reconstruct

the entire process of manufacturing for every individual lot in case of problems. Necessary is

also an ”Out of Specification” (OOS) SOP. A periodic review of the protocols, mostly

annually, yields in addition valuable information about small shifts in quality parameters and

countermeasures can be contemplated.

Evaluation: quality control

The requirements for quality control, which have been discussed at length before in context

with GLP, are resummarised in figure 15. In many cases, the sampling procedures and

stability testing fall also under the responsibility of the QC unit ( fig.16 )
Other aspects

In addition to the more or less official recommendations of GMP, there is a concomitant,

rather large amount of accompanying rules and guide-lines, most of them semi-official. There

are regulations available for establishing a master qualification plan (DIN-ISO), quality

assurance systems (DIN-ISO), PIC documents for inspection, validation etc., ICH documents

on purity, stability testing etc. and a whole set of GLP and GCP guidelines of the EC. They

will not be discussed in the context, but their existence and at least partial relevance to herbal

medicinal products should be mentioned.

Most frequent deviations and defaults

An analysis of warning letters of the FDA, a public instrument of this agency to enforce GMP

compliance lists the following, most frequent defaults (8, Fig. 17).

The list provides some hints to where special attention is needed to improve GMP status.

Most of the listed deviations can be remedied by changing organisational procedures and

investing thought and effort, not necessarily money. It is my opinion, that adequate GMP

manufacturing of herbal medicinal products is reasonabvly possible everywhere on the globe,

not just in highly industrialized areas of the first world.