Current Good Manufacturing Practices (cGMP) For Herbal Drugs: India has a very ancient history of herbal drugs. Indian land is like a gold mine for various medicinal plants. Nowadays demand for herbal products goes on increasing in the global market. Many synthetic drugs, active constituents are also isolated from medicinal plants. But the quality control of these herbal drugs/products is an important issue not only for the consumers but also for regulators and manufacturers Laws, regulations, and guidelines: stipulating requirements of good manufacturing practice (GMP) of herbal products differ worldwide. Malpractice in the quality of herbal products can be done in terms of adulterations, substitutions, misidentification/mislabeling of herbal ingredients, and heavy metal/pesticide/microbial contaminations. Therefore the implementation of GMP to herbal drugs is one of the ways to ensure that the manufacturing process is carried t to meet the prescribed standards, quality control measures are adequately followed, and the finished products are of acceptable quality before they are released in the market for selling.
The Medicine Inspector of the Department of Health and Social Security of England, in consultation with other interested bodies, compiled the guide to GMP also known as the Orange Guide. The first edition of the guide was published in 1971, the manufacturing of drugs carried out under the Medicines Act. Further new editions were published day by day. Many countries have legislated their GMP guidelines that correspond with their legislation. In 1980, US FDA began publishing series of guidance documents that have a major effect on our interpretation of current GMP (cGMP). The World Health Organization (WHO) version of GMP is used by pharmaceutical regulators and the pharmaceutical industry in over one hundred countries worldwide.
WHO Supplementary guidelines for the manufacture of herbal medicinal products were issued in 1996. Various products specific good manufacturing practice (GMP) guidelines covering herbal medicines were developed by several World Health Organization (WHO) the Member States and by the European Union. They covered several issues relevant to the production and quality control of herbal medicines in more detail. Each Member State should develop its own national GMP for manufacturing herbal medicines according to the country’s actual situation.
WHO Guidelines on cGMP For Herbal Medicines
In India Drug & Cosmetics Act, schedule T covers the minimum requirements for the manufacture & quality control of herbal medicinal products.
The World Health Organization (WHO) version of GMP is also used worldwide. WHO GMP guidelines focus on general requirements for quality assurance & quality control in the manufacturing of herbal medicinal products.
cGMP is basic common manufacturing sense formalized into an International pharmaceutical convention covering every aspect of ‘current Good Manufacturing Practise’ and its consequent ‘quality assurance’. The main plank of cGMP is an inspection by the national body responsible for enforcement of quality standards in medicines which in our case, is the British Government Department of Health’s the Medicines and Healthcare products Regulatory Agency (MHRA). CGMP controls starting materials, intermediates, and finished goods.
Importance Of GMP
Herbal medicines have inherent complexity as they are obtained from varied geographical and/or commercial sources and the often variable methods of cultivation, so they may vary in chemical composition and properties. Therefore to maintained/assure the quality of finished herbal products the application of GMPs in the manufacture of herbal medicines is essential.
|Herbs:||Herbs include crude plant materials such as leaves, flowers, fruits, seeds. stem wood, bark, roots, rhizomes, or other parts of the higher plant or derived from lower plant-like lichen, algae, fungi, which may be entire, fragmented, or powdered.|
|Medicinal plant:||Plants used for medicinal purposes,|
|Herbal materials:||It includes herbs, fresh juices, gums, fixed oils, essential oils, resins, and dry powders of herbs.|
|Herbal preparations:||It includes comminuted or powdered herbal materials, or extracts, tinctures, and fatty oils of herbal materials.|
|Finished herbal products:||Finished herbal products consist of one or more herbal preparations made from one or more herbs. Products containing different plant materials are called “mixture herbal products”.|
|Herbal medicines:||Herbal medicines include herbs, herbal materials, herbal preparations, and finished herbal products.|
|Active ingredients:||Constituents with known therapeutic activity, when they have been identified.|
|Markers:||Marker substances are reference substances that are chemically defined constituents of herbal material.|
|Therapeutic activity:||It refers to the successful prevention, diagnosis, and treatment of physical and mental illnesses, improvement of symptoms of illnesses, as well as beneficial alteration or regulation of the physical and mental status of the body and development of a sense of general well-being.|
Good Manufacturing Practices (GMP) Components
- Quality assurance in the manufacture of herbal medicines
- Good manufacturing practices for herbal medicines
- Sanitation and hygiene
- Qualification and validation
- Product recalls
- Contract production and analysis
- Personal hygiene
- Good practices in production
- Good practices in quality control
1. Quality assurance in the manufacture of herbal medicines
For characterization of herbal medicines the modern analytical techniques (especially high-performance thin-layer chromatography (HPTLC), gas chromatography (GC), high-performance liquid chromatography (HPLC), capillary electrophoresis (CE), mass spectrometry (MS), and amic absorption (AA) are used. But for quality assurance the control of starting materials, storage, and processing also require.
2 Good manufacturing practices for herbal medicines
Various guidelines for Cultivation and collection of medicinal plants, the first step where the application of GMP starts, and the general principles of GMP are detailed in the WHO parent guideline
3. Sanitation and hygiene
Herbal materials may contain microbiological contaminants, because of their origin and during harvesting and processing. In general, a high level of sanitation and hygiene during manufacture is necessary, to avoid alterations and to reduce contamination.
Water supply to the manufacturing unit should be monitored, and, if necessary treated appropriately to ensure consistency of quality.
To maintain a high standard of hygiene in the manufacturing area, waste from the manufacturing unit should be disposed of regularly.
4. Qualification and validation
Qualification of critical equipment, process validation, and change control is particularly important in the production of herbal medicines with unknown therapeutically active constituents. In this case, the reproducibility of the production process is the main means for ensuring consistency of quality, efficacy, and safety between batches.
The written procedure should specify critical process steps and factors (such as extraction time, temperature, and solvent purity) and acceptance criteria, as well as the type of validation to be conducted (e.g. retrospective, prospective or concurrent) and the number of processes runs.
A formal change control system should be established to evaluate the potential effects of any changes on the quality of the herbal medicines, particularly the content of the active ingredients.
A well-trained and/or experienced person is required for handling complaints and deciding on the measures to be taken in the specific features of the quality control of herbal medicines.
Two types of complaints:
- Product quality complaints
- Adverse reaction/ events.
Product quality complaints may be due to faulty manufacture, product defects or deterioration as well as, adulteration of the herbal material. These complaints should be recorded in detail and the causes thoroughly investigated. (e.g. by comparison with the reference samples kept from the same batch). There should also be written procedures to describe the action to be taken.
The second type of complaint, reports of any adverse reaction/event should be entered in a separate register by national and international requirements. An investigation should be conducted to find out whether the adverse reaction is due to a quality problem and whether it is a new observation. In either case, complaint records should be reviewed regularly to detect any specific or recurring problems requiring special attention and possible recall of marketed products.
The licensing authority should be kept informed of any complaints leading to a recall or restriction on supply and the records should be available for inspection.
6. Product recalls
The product recall procedure depends very much on the national regulations. There should be a standard operating procedure (SOP) for the storage of recalled herbal medicines in a secure segregated area, complying with the requirements.
7. Contract production and analysis
The contract partner should have adequate premises and equipment for the production of herbal medicines according to GMP. Validated methods should be applied for cleaning the equipment and premises carefully before using them. Manufacturing departments should separate the plant raw material that will be cut or powdered for use in the preparation of medicines.
Technical aspects of the contract should be drawn up by competent persons suitably knowledgeable on the specific characteristics of herbal medicines, including their production and quality control testing.
At least one member of the self-inspection team should possess a thorough knowledge of herbal medicines.
The release of herbal medicines should be authorized by a person who has been trained in the specific features of the processing and quality control of herbal materials, herbal preparations, and finished herbal products.
Personnel dealing with the production and quality control of herbal medicines should have adequate training on the specific issues relevant to herbal medicines.
The personnel should have adequate training in appropriate fields such as pharmaceutical technology, taxonomic botany, phytochemistry, pharmacognosy, hygiene, microbiology, and related subjects (such as traditional use of herbal medicines).
Training records should be maintained and periodic assessments of the effectiveness of training programs should be made.
11. Personal hygiene
Personnel entrusted with the handling of herbal materials, preparations, and finished products should be required to have a high degree of personal hygiene and there should be training programs & their record. Personnel with infectious diseases or skin diseases should not work. Written procedures listing the basic hygiene requirements should be made available.
Personnel must be protected from contact with toxic irritants and potentially allergenic plant materials using adequate protective clothing. They should wear suitable gloves, caps, masks, work suits, and shoes throughout the whole procedure of manufacture.
Premises should be designed, located, constructed, adapted, and maintained to suit the operations to be carried out according to GMP.
Herbal materials and herbal preparations have special importance because of their potential for degradation and infestation with certain pests as well as their sensitivity to microbiological contamination.
Special attention should be paid to cleanliness and good maintenance. Any accidental spillage should be cleaned up immediately so that minimizes the risk of cross-contamination of other materials and should be reported.
Set-up of storage depends on the type of materials stored. The areas should be well labeled.
Storage areas should be laid out to permit effective and orderly segregation of the various categories of materials stored, and to allow rotation of stock. Different herbal materials should be stored in separate areas.
Incoming fresh herbal materials should be unless specified. If appropriate, they should be stored between 2 °C and 8 °C, whereas frozen materials should be stored below-18 °C.
To reduce the risk of mold formation or fermentation, store them in aerated rooms or containers using natural or mechanical aeration and ventilation. These areas should protect against the entry of insects or animals, especially rodents.
Herbal materials, even when stored in fiber drums, bags, or boxes, should be stored off the floor and suitably spaced to permit cleaning and inspection.
The storage of plants, extracts, tinctures, and other preparations may require special conditions of humidity and temperature or protection from light. Appropriate steps should be taken to ensure that these conditions are provided, maintained, monitored, and recorded.
Herbal materials, including raw herbal materials, should be kept in a dry area protected from moisture and processed following the principle of “first-in, first-out” (FIFO).
Particular attention is given to processing products that generate dust. When heating or boiling of the materials is necessary, a suitable air exhaust mechanism should be employed to prevent the accumulation of fumes and vapors.
Adequate precautions should be taken during the sampling, weighing, mixing, and processing of medicinal plants to avoid cross-contamination, for example, by use of dust extraction and air-handling systems to achieve the desired differential pressure and net airflow.
Processing of herbal materials may generate dust or microbiological contamination so effective cleaning of the equipment is important.
Vacuum or wet-cleaning methods are preferred. If wet-cleaning is done, the equipment should be dried immediately after cleaning to prevent the growth of microorganisms. Cleaning with compressed air and brushes should be avoided if possible and, if used, should be done with care, as these methods increase the risk of product contamination.
As a rule non-wooden equipment should be used unless it is a requirement of a traditional method of manufacture, where it is necessary to use traditional equipment (such as wooden implements, clay pots, pallets, hoppers, etc.), this should be dedicated, unless otherwise justified.
All incoming herbal materials should be quarantined and stored under appropriate conditions.
Only permitted substances should be used for fumigation, and allowable limits for their residues together with specifications for the apparatus used should be set according to the national regulations.
Reference samples and standards
The reference standard for herbal medicine may be a botanical sample of the herbal material; a sample of the herbal preparation, for example, extract; or a chemically defined substance, for example, a known active constituent, a marker substance, or a known impurity. The reference standard should be of a quality appropriate to its purpose.
If the herbal medicine is not described in a recognized pharmacopeia, a herbarium sample of the flowering or fruiting top of the whole medicinal plant or part of the medicinal plant (for example, if the whole medicinal plant is a tree) should be available.
All reference standards should be stored under appropriate conditions to prevent degradation. Their expiry and/or revalidation date should be determined and indicated.
Sometimes the more detailed information may be needed on aspects of collection or agricultural production. For instance, the selection of seeds, conditions of cultivation, and harvesting are important in producing herbal medicines of reproducible quality. Their characterization (a detailed evaluation of the botanical and phytochemical aspects of the medicinal plant) is therefore essential to allow the establishment of specifications that are both comprehensive and relevant.
For this reason, in addition to the data called for, the specifications for herbal materials should as far as possible include, as a minimum, the following information:
- The family and botanical name of the plant are used according to the binomial system (genus, species, variety, and the authority, i.e. the reference to the originator of the classification, for example, Linnaeus). It may also be appropriate to add the vernacular name and the therapeutic use in the country or region of origin of the plant.
- Details of the source of the plant, such as country and/or region of origin (also state and province or collected from the wild and, where applicable, method of cultivation, dates, and conditions of harvesting (for example, whether there was extreme weather), collection procedures, collection area, and brand, quantity, and date of pesticide application, as required by the WHO Guidelines on good agricultural and collection practices.
- Suitable identity tests including such as TLC or other chromatographic fingerprints for known active ingredients. A reference sample should be available for identification purposes.
- Limit tests such as dry residue of liquids, Ash value, water-soluble extractives, moisture/water content, and loss on drying.
- If starting materials are official in any pharmacopeia, reference to that pharmacopeia should be made & if starting material is comprised of genetically modified organisms, it should comply with national or international regulations & the label should indicate this information.
Finished herbal products:
- The control tests and specifications for the finished herbal product should be such as to allow the qualitative and quantitative determination of the main active constituents.
- The processing instructions should describe the different operations performed on the plant material, such as drying, crushing, milling, and sifting & also include the time, tempera s required in the drying process, and the methods to be used to control fragment or particle size.
- If the plant should be processed fresh, without drying, the reasons and criteria determining the use of fresh material should be stated.
- For the production of processed extracts, the instructions should specify details of any vehicle, the durations and temperatures needed for extraction, and any concentration stages and methods that may be required.
- Any treatment, such as fumigation, used to reduce fungal or microbiological contamination and steps of blending should be documented.
- Steps in the processes of blending and adjustment to reach defined contents of pharmacologically active constituents should be documented.
16. Good practices in production
To ensure not only the quality but also the safety and efficacy of complex products of biological origin such as herbal medicines, the steps in their production must be clearly defined
For medicinal plants:
- The first critical step of their production, Le where the application of these guidelines starts, should be designated. The rationale for this designation should be stated and documented. However, for processes such as extraction, fermentation, and purification, this rationale should be established on a case-by-case basis.
- Collection/cultivation and/or harvesting of medicinal plants should follow other relevant guidance such as the WHO Guidelines on good agriculture and collection practices (GACP) for medicinal plants or national guidelines.
- Generally, post-harvest processing including primary cutting is (or should be) covered by GACP. If cutting and comminuting considerably reduce the probability of detection of adulteration or mix-up of herbal materials, the application of these supplementary guidelines may be extended to encompass these steps.
- When the active ingredient, consists exclusively of comminuted or powdered herbs, application of these guidelines starts at the physical processing following primary cutting and comminuting and includes packaging.
- When herbal extracts are used, the principles of these guidelines should apply to any production step following post-harvest processing.
- In the case of finished herbal products manufactured by fermentation, the application of GMP should cover any production step following primary cutting and comminuting. Particular attention should be given to the introduction of cells from a cell bank into the fermentation process
- On arrival at the processing facility, the herbal material should be promptly unloaded and unpacked. During this operation, the herbal material should not come into direct contact with the soil. Moreover, it should not be exposed directly to the sun (except where this is a specific requirement, for example, for sun-drying) and it should be protected from rain and microbiological contamination.
- Attention should be paid to “classification of clean area requirements taking into account the possible high degree of initial microbial contamination of herbal materials. Specific and detailed requirements should be developed to cover microbial contamination of equipment, air, surfaces, and personnel, and also for restrooms, utilities, ancillary, and support systems (for example, water, and compressed air).
- Care should be taken to choose cleaning methods appropriate to the characteristics of the herbal materials being processed. Washing dried herbal materials with water is generally inappropriate. When it is necessary to clean them, an air duster or air shower should be used Where immersion of herbal materials in water or other appropriate agents (such as disinfectants) for cleaning is unavoidable (for example, to eliminate suspected coliform bacteria), it should be kept to a minimum.
- The presence of plant materials from different species and varieties, or different plant parts should be controlled throughout the entire production process to avoid contamination unless it is assured that these materials are equivalent.
- If time limits are specified in the master production instructions, these limits should not be, exceeded, to ensure the quality of intermediates and finished products. The less is known about the constituents responsible for the therapeutic activity, the more strictly this rule should be obeyed.
Mixing of batches and blending:
- Herbal medicines with constituents of known therapeutic activity are often standardized (Le adjusted to a defined content of such constituents). The methods used to achieve such standardization should be documented. If another substance is added for these purposes, it is necessary to specify, as a range, the quantity that may be added. The blending process should. be adequately controlled and documented and the blended batch should be tested for conformity with established specifications where appropriate.
- Batches should be mixed only if the homogeneity of the mixture can be guaranteed. Such processes should be well documented.
- Out-of-specification batches of herbal medicines should not be blended with other batches to meet specifications, Every batch incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications before blending.
- Where particular physical attributes of the material are critical, blending operations should be validated to show the uniformity of the combined batch. Validation should include testing of critical attributes (for example, particle size distribution, bulk density, and tapped density) that may be affected by the blending process.
- The expiry date of the blended batch should be chosen according to the date of manufacture of the oldest batch in the blend.
17. Good practices in quality control
The personnel of quality control units should have the necessary expertise in herbal medicines to enable them to carry out identification tests and recognize adulteration, the presence. of fungal growth or infestations and lack of uniformity in a consignment of herbal materials.
The quality control of the herbal material, herbal preparations, and finished herbal products should establish their quality but this does not imply the control of every single constituent.
Because herbal materials are an aggregate of individual plants and/or different parts of the same plant and thus have an element of heterogeneity, sampling should be out with special care by personnel with the necessary expertise.
Further advice on sampling and visual inspection is given in the WHO document Quality control methods for herbal materials.
The identity and quality of herbal material, herbal preparations, and finished herbal products should be tested as described in the Quality control methods for herbal materials. Moreover, each country should develop this basic requirement for technical equipment further, according to the country’s needs.
Herbal material, herbal preparations (including extracts), and finished herbal products can be categorized as follows:
- the active constituents are identified, and maybe quantified as such;
- the main group of components that contribute to the activity (ie the constituents with known therapeutic activity) are known and can be quantified as a total (for example, essential oils) or calculated using a representative substance belonging to the group (for example, flavonoids); c. the former are not identified and/or are not quantifiable, but marker substances are;
- others, where quantification (i.e. specification for a certain quantity of a constituent) is not applicable or feasible.
Identification methods may be based on:
- physical and, if applicable, macroscopic (organoleptic) and microscopic tests;
- chromatographic procedures (TLC, HPLC, HPTLC or gas. liquid chromatography (GLC)), spectrometric techniques (ultraviolet-visible (UV-VIS), IR, nuclear magnetic resonance (NMR), MS); and/or;
- chemical reactions,
If the expiry date for a herbal material or herbal preparation is given, some stability data to support the proposed shelf-life under the specified storage conditions should be available.
The fingerprint methods are used for stability studies.
Normally the first three production batches should be included in the stability-monitoring program to confirm the expiry date.
Packaging materials and labeling:
All packaging materials, such as bottles, containers & closures should be thoroughly cleaned & dried & stored properly.
There should be adequate information on the label to inform the users of the composition of the product, indications or actions, directions for use, cautions and adverse reactions if any, and the expiry date.
The qualitative and quantitative particulars of the active ingredients in herbal materials and preparations should be expressed in the following ways:
For herbal materials and preparations consisting of powdered herbal materials: The quantity of the herbal material must be stated or, if constituents with known therapeutic activity are unidentified, the quantity of the herbal material/herbal preparation should be stated.
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