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cGMP Audit Checklist + Plant Extraction Audit Items

GENERAL COMPANY INFORMATION Information Comment

Y N N/ACheck in the ‘Y’ column if information is collected, confirmed, or reviewed. Check in the ‘N’ column if it is not. Check in the ‘N/A’ column if it does not apply. Comments are optional depending on data collected.

Company Background Primary Location/Site Audited Facility description and sq footage Pertinent facility details:

Registrations Personnel involved in audit with titles Quality Unit Reporting Structure and Organizational Charts

Inspection History / FDA-483s General appearance of facility

cGMP Audit Checklist (template) of 29


QUALITY SYSTEM – Has the Quality Unit fulfilled responsibilities to review and approve procedures related to production, quality control, and quality assurance and assure procedures are adequate for their intended use? Does the firm have written and approved procedures and documentation resulting from these procedures (i.e. record keeping procedures adequate?) Assess data collected to identify quality problems which may link to other major systems for inspectional coverage. Criteria Evaluated Meets Comment

Y N N/AQuality Unit Responsibilities Organization Chart up to date and shows adequate detail

The responsibilities of the Quality Assurance unit defined in SOP and fully followed.

Quality Unit has authority to review records and investigate errors.

QA routinely conducts internal audits. There is an established procedure covering the delineation of Quality Unit responsibilities among all contracted parties. (e.g. a Quality Agreement or other contractual arrangement)

There is a system for managing and controlling documents

There is an established change control procedure. Change control is documented, evaluated, and approved. The need for revalidation is assessed.

Sub-contracted laboratories are inspected and qualified.

There is an established investigation procedure. Discrepancy and failure investigations related to manufacturing and testing are documented, evaluated, investigated in a timely manner; includes corrective actions where appropriate.

There is an established procedure ensuring that rejects investigations are expanded where warranted. Corrective actions are taken where appropriate.

There is an established corrective and preventative action procedure.

There is an established procedure stating that stability failure investigations are expanded where warranted.

There is an established procedure for complaints. Complaints reviews are documented, evaluated, investigated in a timely manner and include corrective actions where appropriate.

Personnel/Training There is sufficient staff to perform the functions of this laboratory.



Criteria Evaluated Meets CommentY N N/A

A written training procedure is available and it is followed.

Personnel records indicate they have appropriate education, training, and experience to perform assigned functions.

Personnel training records include documentation of cGMP orientation and ongoing cGMP training according to training SOP.

Personnel training records include documentation of training related to their job responsibilities.

Training and retraining is performed with sufficient frequency.

Standard Operating Procedures There is an established SOP system. The Table of Contents is attached.

All SOPs are current as defined in the company SOP on SOPs.

SOPs reviewed meet requirements of the SOP on SOPs.

Personnel are trained on SOPs pertaining to their job and re-trained when SOPs are revised.

SOPs are followed



FACILITY AND EQUIPMENT SYSTEM


Facility – General External access to the facility is restricted and monitored.

The laboratory area is adequate in size, lighting, workspace and ventilation.

The laboratory facilities appear organized, clean and well-maintained

The facility is designed and utilized in a manner to provide controlled flow of materials to prevent mix-ups and contamination.

There is an established rodent and pest control program and it is followed.

Food, drink and smoking are not allowed in the laboratory areas.

There is power supply back up in case of power failure.

Refrigerated storage is available and the temperature is monitored.

Freezer storage is available and the temperature is monitored.

The sample storage areas are well defined and access is controlled.

Equipment, Instruments, and Computers A Validation Master Plan is written, approved, and up to date.

The status of computer validation projects agrees with the Validation Master Plan.

Part 11-gap analysis has been conducted and a Master Plan is available. (predicate rule applicability)

There is a written calibration plan Calibrations are performed and documented according to schedule.

Equipment is spot-checked and all calibrations are current.

Daily checks are performed on balances and other frequently used instruments as described in SOPs.

IQ/OQ/PQ is performed on major equipment.Equipment preventative maintenance is performed according to schedule.

Computer system security is maintained. There are computer back-up, archival, and recovery systems.

There is a disaster recovery program to ensure the integrity of computer data.




There are procedures for computer system maintenance

There are procedures for periodic reviews of computer software.

There is a computer system change control procedure.

When spreadsheets are developed (or other electronic mechanisms) for the collection and tracking of test results, the electronic spreadsheets are validated.

There is an established procedure for correcting computer data entry errors.

Data acquisition systems are well defined and validated.

Data acquisition system is Part 11 compliant.

MATERIAL SYSTEM (Laboratory Samples and Reagents)

Criteria Evaluated Meets Comment (Optional)Y N N/AMSDS are available to personnel Samples intended for analyses are assigned a unique ‘sample tracking’ number and appropriately labeled.

Records are maintained for the receipt and inventory control of reagents, samples, and reference standards

Reagents, reference standards, and samples are properly labeled. (Reagents and standards are labeled with expiry dates, as appropriate.)

.

Reagents, reference standards, and samples are properly stored.

Reagents and reference standard expiry dates are tracked.

Sample storage conditions are monitored There are procedures for disposal of samples.

There is a designated retain storage area and system for storing retains.

LABORATORY CONTROLS (including STABILITY and MICROBIOLOGY TESTING)

Criteria Evaluated Meets Comment (Optional)Y N N/A

Laboratory Controls – General



Criteria Evaluated Meets Comment (Optional)Y N N/ASampling hoods are clean, free of clutter, and well-maintained with proper environmental controls, where appropriate.

Glassware is adequately cleaned and controlled to prevent contamination of lab samples.

There is adequate control of chromatography columns

Equipment logbooks are maintained and include record of use, cleaning, maintenance, repairs, calibration, etc with persons performing operations.

Raw laboratory data notebooks are bound books or analytical sheets for which there is accountability.

Notebook entries are neat, well organized, legible and organized.

Upon review of weighing, dilutions, and calculations in notebooks, there are no rewritten records or use of correction fluid to conceal errors.

Written entries that are changed are explained, signed and dated.

Written test specifications are available and followed.

Written test methods are available and followed.

There is a system in place that assures client test methods are followed.

Laboratory records include sample description, ID#, and source; statement of test method used and source; sample description and wt. if appropriate; all data generated, calculations, reference standard ID, signature of analyst and date performed; results; signature of reviewer confirming accuracy, completeness, and compliance with established standards.

Laboratory records include description of modification of test procedures with justification and data to prove accuracy and reliability of change.

Records of reference standard prep and testing are available.

Reference standard certification data is available.

Stock solutions are not reused unless stability is determined.

Stock solutions stored in refrigerators are appropriately identified.



Criteria Evaluated Meets Comment (Optional)Y N N/AThere are established methods for analytical methods validation.

The laboratory performs accuracy, sensitivity, specificity and reproducibility (and precision, linearity, ruggedness, system suitability, etc. to validate methods.

There are established procedures for analytical methods transfer.

There is a written OOS procedure for investigation of lab errors, non-process related operator errors, and process related or manufacturing errors.

A full scale inquiry including QA as well as laboratory personnel s conducted for multiple OOS results.

When a failure investigation is inconclusive, the firm does not release based on average results (2 tests plus failure); does not use outlier test for chemical tests; does not use a re-sample to assume a sampling or preparation error but may conduct a retest of different tablets from the same sample when a retest is considered appropriate.

There is an aberrant data procedure available and it is followed.

Investigations are performed in a timely manner.

The companies Retesting SOP is compliant and scientifically sound.

Micro lab SOPs describe the procedure for investigation of sterility positives.

Laboratory Controls – Stability There is adequate storage capacity in the stability chambers.

Stability chambers are qualified and environmental conditions are mapped/monitored.

There is back-up power available for stability storage and it is routinely tested.

Stability storage chamber calibration is up to date.

There is no evidence of stability protocol deviations.

QA/QC provides oversight of stability testing and reporting activities.

Stability results are pulled within 7 days of the scheduled pull date.

Stability tests are completed within 30 days of the pull date.



Criteria Evaluated Meets Comment (Optional)Y N N/AStability results are summarized and reports accurately reflect raw data.



DOCUMENTS REVIEWED:



Plant Extraction and Processing Information

Comment

Y N N/A

Check in the ‘Y’ column if information is collected, confirmed, or reviewed. Check in the ‘N’ column if it is not. Check in the ‘N/A’ column if it does not apply. Comments are optional depending on data collected.

o General plant extraction procedures and documentation o Organizational structure o Company’s quality assurance/ management polices and systems to insure

environmental regulations and standards (specific areas)

o extraction plants for herbs including hammer mills and screw-mixers for the preparation of herbal raw material and distillation plants for recovering extraction solvents

o multipurpose reactors if any o crystallizers o distillation apparatus o condensing plant o retained extraction plants of different types if any o large scale chromatographic columns if any o clean-room centrifuges of different type o location of filter dryers or tray dryers o toll manufacturing mixers o analytical methods and quality control tests on incoming materials o list of all grower(s) and/or supplier(s) (including names and addresses). The

following items should be provided for each grower/supplier, if available:− Harvest location− Growth conditions− Stage of plant growth at harvest− Harvest time− Collection, washing, drying, and preservation procedures− Handling, transportation, and storage conditions

o determination of contaminants like pesticides, adventitious agents, or other adulterants

o Lot comparison data to demonstrate process consistency in yield

1. Description of Botanicals Used (§ 312.23(a)(3)(i))• Morphological and anatomical description (including gender, if applicable) and a photograph of the plant or plant part, alga, or macroscopic fungus used

• Natural habitat and geographical distribution of the plant, alga, or macroscopic fungus

• Current sources of the plant, alga, or macroscopic fungus, including its geographical location and whether it is cultivated or harvested from the wild




Comment

Y N N/A


• A statement indicating whether the species is any of the following:− Determined to be endangered or threatened under the Endangered Species

Act or the Convention on International Trade in Endangered Species of Wild Fauna and Flora;

− Entitled to special protection under some other Federal law or international treaty to which the United States is a party;

− The critical habitat of a species that has been determined to be endangered or threatened

2. History of Use (If Any) (§ 312.23(a)(3)(ii), (a)(9))• Method of preparation, processing, and formulation• Routes, schedules, and doses of administration• Medical claims• Contraindications and adverse events associated with use in humans and animals• Traditional geographical areas and populations in which such use occurred• A description of the similarities and/or differences between the traditional preparation and the proposed clinical formulation

3. Current Investigational Use (If Any) (§ 312.23(a)(3)(ii), (a)(9))• Proposed therapeutic claim and dose regimen (mg/kg/dose and dose/day)• All available information in the literature that addresses the proposed therapeutic claim, including both positive and negative studies

Botanical Raw Material: CMC Requirements

• Identification by trained personnel of the plant, plant parts, alga, or macroscopic fungus used, including organoleptic, macroscopic, and microscopic examination. The identification should be done against a voucher specimen (reference specimen). If more than one variety of a given species is used, each should be specified. A sample of the plant, plant parts, or other botanical materials should be retained and stored under appropriate conditions by the raw material supplier and botanical drug substance manufacturer for each batch. These samples will be used for verification of identity, if needed.

• A certificate of authenticity

• A list of all grower(s) and/or supplier(s) (including names and addresses). The following items should be provided for each grower/supplier, if available:

− Harvest location− Growth conditions− Stage of plant growth at harvest− Harvest time− Collection, washing, drying, and preservation procedures− Handling, transportation, and storage conditions




Comment

Y N N/A


Botanical Drug Substance: CMC Requirements• A qualitative description of the drug substance, including the name, appearance, physical and chemical properties, active constituent (if known), biological activity (if known), and clinical indication (if known) of each botanical raw material. If the active constituent, biological activity, and/or clinical indication is unknown, the IND sponsor should clearly so state. In the case of a multi-herb substance, the sponsor should state whether the drug substance is prepared by combining individually processed botanical drug substances or by processing combined botanical raw materials.

• The quantitative description (strength) of the drug substance. Historically, the strength of a botanical drug substance is expressed simply as the absolute dry weight of the processed substance. The batch size and the yield of the process, relative to the botanical raw material, also should be indicated. Furthermore, where the active constituents or other chemical markers are known and measurable, the amount in which they are present in the botanical drug substance should be declared. For a multi-herb substance, its composition should be expressed in terms of the relative ratio of the individually processed botanical drug substances or of the botanical raw materials before processing, whichever is appropriate.

• The name and address of the drug substance manufacturer (processor).

• A description of the manufacturing process for the botanical drug substance. The description should include the quantity of botanical raw material, solvents, extraction and/or drying, and yield. The yield of the process, expressed as the amount of the original botanical raw material relative to the amount of the extract, also should be indicated. If more than one botanical raw material is introduced to produce a multi-herb substance, the quantity of each raw material and the sequence of addition, mixing, grinding, and/or extraction should be provided. If a multi-herb substance is prepared by combining two or more individually processed botanical drug substances, the process leading to each botanical drug substance should be described separately.




Comment

Y N N/A


• The quality control tests performed on each batch of the drug substance, the analytical procedures used, and the available test results. These tests should include, but need not be limited to, the following attributes:

– Appearance

– Chemical identification by spectroscopic and/or chromatographic fingerprints. Examples of spectroscopic methods include ultraviolet, infrared, Fourier transformed infrared, and mass spectroscopy. Examples of chromatographic methods include high performance liquid chromatography (HPLC), HPLC with diode array detection, thin layer chromatography (TLC), 2-dimensional-TLC, and gas chromatography.– Chemical assay (i.e., assay) for active constituents or characteristic markers. If several botanical raw materials are combined to produce a multi-herb substance and a quantitative determination of each individual active constituent or marker is infeasible, a joint determination can be made for several active constituents or markers. When multiple active constituents or markers are known, they should be chemically characterized and their relative amounts should be defined.

– Biological assay (when the active chemical constituent(s) are not known or quantifiable), if available. If the botanical drug substance is considered potent (i.e., highly active), toxic, addictive, or has abuse potential (e.g., ephedra or marijuana), an assay for biological activity and/or a chemical assay for the active constituent(s) should be performed.

– Strength by dry weight (equivalent to botanical raw material)

– Heavy metals

– Microbial limits

– Animal safety test, if applicable

• A description of the container/closure in which the botanical drug substance is to be stored and/or shipped.

• Available stability data on the drug substance. The sponsor should develop stability-indicating analytical methods and conduct stability studies as the IND progresses




Comment

Y N N/A


• The container label, which should reflect the qualitative and quantitative description of the botanical drug substance, as discussed above, and recommended storage conditions. Examples of labeling for single-herb and multi-herb substances are shown below:

Single-herb substance:− Expressed in terms of yield:

Senna, 10 kg, equivalent to 80 kg of dried leavesorSenna, 10 kg, 8:1 (w/w) powdered extract of dried leaves

− Expressed in terms of active constituents:Senna, 10 kg extract, containing 2 kg of hydroxyanthracene glycosides(sennosides), calculated as sennoside B

− Expressed in terms of chemical markers:Valerian, 10 kg extract, containing 0.1 kg valerinic acid




Comment

Y N N/A


• The quality control tests and analytical procedures applied by the botanical raw material supplier and the proposed acceptance criteria. These tests should include, but need not be limited to, the following attributes:

– Botanical identification– Chemical identification by spectroscopic and/or chromatographic fingerprint– Chemical identification for active constituents or characteristic markers if active constituents are not known– Assay for active constituents or characteristic markers if active constituents are not known– Biological assay (when the active chemical constituents are not known or quantifiable), if available– Heavy metals– Microbial limits– Residual pesticides, including parent pesticides and their major toxic metabolites– Adventitious toxins (e.g., aflatoxins)– Foreign materials and adulterants

In some cases (e.g., when the botanical raw material undergoes further processing to prepare the botanical drug substance), reduced testing may be appropriate for certain assays (e.g., heavy metals), if these assays are routinely performed on the botanical drug substance. If some of these tests cannot be performed by the raw material supplier, the botanical drug substance manufacturer should perform the tests upon receipt of the botanical raw material.

A photocopy of the voucher specimen (reference specimen) of the botanical raw material used in identification, fingerprinting, and other comparative and non-comparative tests

A certificate of analysis for representative batch(es) of the botanical raw material

A description of the storage conditions, container/closure system, and temperature

Botanical Drug Substance: Phase III IND CMC Requirements A qualitative and quantitative description of the drug substance and the name and address of the manufacturer (see section VIII.B.2).




Comment

Y N N/A


A chemical identification for the active constituents or characteristic markers in the drug substance, if possible. If the chemical identity is unknown, a representative spectroscopic and/or chromatographic fingerprint may suffice.

Appropriate acceptance specifications (tests, test procedures, and acceptance criteria) for the botanical raw material, similar to the list of quality control specifications in section IX.B.1.a, established by the botanical drug substance manufacturer. Upon receipt of each batch of the raw material and its certificate of analysis, the manufacturer should, at a minimum, conduct an identification test and assay.

A description of the manufacturing process for the botanical drug substance. The description should include the quantity of botanical raw material, equipment, solvents, temperature/time for mixing, grinding, extraction and/or drying, yield, and in-process controls. The yield of the process, expressed as the amount of the original botanical raw material relative to the amount of the extract, also should be indicated. If more than one botanical raw material is introduced to produce a multi-herb substance, the quantity of each raw material and the sequence of addition, mixing, grinding, and/or extraction should be provided. If a multi-herb substance is prepared by combining two or more individually processed botanical drug substances, the process leading to each botanical drug substance should be described separately.




Comment

Y N N/A


The quality control tests performed on each batch of drug substance, the analytical procedures used, and the proposed acceptance criteria. These tests should include, but need not be limited to, the following attributes:

– Appearance

– Chemical identification by spectroscopic and/or chromatographic fingerprints

– Chemical identification for the active constituents or, if unknown, the characteristic markers

– Chemical assay for the active constituents, or the characteristic markers if the active constituents cannot be determined. If several botanical raw materials are combined to produce a multi-herb substance and a quantitative determination of each individual active constituent or marker is infeasible, a joint determination can be made for several active constituents or markers. When multiple active constituents or markers are known, they should be chemically characterized and their relative amounts should be defined.

– Biological assay (when the active chemical constituents are not known or quantifiable), if available. If the botanical drug substance is considered potent (i.e., highly active), toxic, or addictive, or has abuse potential (e.g., ephedra or marijuana), an assay for biological activity and/or a chemical assay for the active constituent(s) should be performed.

– Strength by dry weight– Residue on ignition– Water content– Residual solvents– Heavy metals– Microbial limits– Animal safety test, if applicable– Residual pesticides– Radioisotope contaminants, if applicable– Adventitious toxins (e.g., aflatoxins)– Endogenous toxins (e.g., pyrrolizidine alkaloids)– Other attributes specific to the botanical raw materials from which the drug substance is derived

• Validation reports of all analytical procedures, where appropriate

• A description of the batch of botanical drug substance designated as the reference standard for use in fingerprinting and other comparative tests

• Batch analysis (i.e., test results for representative batches)




Comment

Y N N/A


• A description of the container and closure used to package the botanical drug substance

• Sufficient stability data on the drug substance to support its safe use during clinical studies; stability-indicating analytical methods

• Information on the container label as described in section VIII.B.2

End of Phase III and pre-NDA Considerations Sponsors must continue to characterize the drug substance and the drug product throughout the entire clinical development program (§ 312.23(a)(7)). By the end of the phase 3 clinical trial, as the sponsor prepares to submit an NDA, the following objectives should be reached:

• Adequate controls for botanical raw materials should be established.

• The manufacturing processes of the drug substance and the drug product should be finalized and validated, and in-process controls should be established. An executed batch record should be available.

• Batch-to-batch consistency should be demonstrated for the botanical drug substance and drug product based on results from all chemical, physical, and biological tests on all relevant batches. To achieve this goal, multiple fingerprints, using a combination of analytical methods with different separation principles and test methods, can be useful. All chemical constituents detected by spectroscopic and/or chromatographic fingerprinting should be qualitatively and quantitatively comparable from batch to batch.

• Appropriate specifications (i.e., tests, analytical procedures, and acceptance criteria), including identification and assay for active constituents, identification and assay for characteristic markers, and/or biological assay (when the active chemical constituent(s) are not known or quantifiable), should be established to control the quality of the drug substance and product. Both the active constituents and the biological assay should be clinically relevant. If the identity of the active constituents is not known or a suitable assay cannot be developed, the characteristic markers should be demonstrated to be clinically relevant by direct or indirect correlation to the clinical outcome.

• Analytical procedures should be properly validated. Analytical procedures used for fingerprinting should be verified for specificity and should be capable of detecting as many chemical classes (e.g., proteins, carbohydrates, fatty acids, small organic compounds) present and as many individual chemical constituents as possible. Additionally, when multiple fingerprints are used, the analytical procedures in combination should be able to demonstrate the mass balance in the test sample, on the basis of the different classes of chemicals and, if appropriate, among the individual constituents detected within a chemical class.




Comment

Y N N/A


• A suitable voucher specimen (reference specimen) for each of the botanical raw materials should be established, along with a reference standard for the drug substance and drug product.

• Stability-indicating analytical methods should be developed to monitor the stability of the drug substance and drug product. The stability of a botanical drug substance or product generally should not be based entirely on the assay of the active constituents, assay of the characteristic markers, or biological assay, because degradants formed during storage from other chemical constituents in the botanical drug substance or product should also be controlled. An analytical method capable of detecting these degradants (such as a spectroscopic and/or chromatographic fingerprint) should be established through exploratory studies by subjecting the drug substance and drug product to stress conditions.

• A biological assay, when used for characterization and quality control of a drug substance and drug product, should be properly validated. The ICH Guideline Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (August 1999) and the USP XXV Biological Tests <111>: Design and Analysis of Biological Assays provide useful information on biological assays. Performing a biological assay calls for the use of a suitable reference standard and, frequently, positive and negative controls. Because biological assays are usually more variable than chemical assays, a relatively higher coefficient of variation is generally justifiable.

• A comparison of the similarities and/or differences in CMC among the nonclinical, clinical, and intended commercial products should be made regarding raw materials, drug substance, and drug product.

• The manufacturing, processing, and controls (receipt, identification, storage, handling, sampling, testing, and approval or rejection of components, drug products, and container closures) for botanical drug products must be in conformance with CGMP as set forth in 21 CFR parts 210 and 211. In addition, the manufacturing, processing, and controls for the botanical drug substance (starting from the botanical raw material) should be in conformance with CGMP because these elements can affect the quality, safety, and efficacy of the drug product. A satisfactory inspection is necessary for NDA approval.




Comment

Y N N/A


• A sponsor should be preparing the submission in the NDA of either an EA or a claim for categorical exclusion from the requirement for preparation of an EA (§ 25.15(a)). Classes of NDAs that are categorically excluded and, therefore, ordinarily do not require preparation of an EA are listed in § 25.31. However, FDA will require at least an EA for any specific action that ordinarily would be excluded if extraordinary circumstances indicate that the specific proposed action may significantly affect the quality of the human environment (§ 25.21; 40 CFR 1508.4). The Agency regards the submission of an NDA for a drug derived from plants taken from the wild as an extraordinary circumstance requiring the submission of an EA. See section VIII.B.6 for additional information. Applicants are encouraged to discuss with the review division any CMC issues regarding a botanical drug prior to the preparation and submission of an NDA.

Q18: What is the GMP status of botanical raw materials (starting materials) in terms ofcompliance and inspection?A18: Starting materials of botanical origin that are used to produce a botanical drug substance should be evaluated for quality. The use of appropriate starting materials and the drug substance manufacturer’s ability to control the source depend on appropriate specifications (tests, analytical procedures, and acceptance criteria). In addition to establishing specifications, manufacturers can achieve adequate quality control of starting materials by applying the principles outlined in FDA’s botanical guidance and by following good agricultural and good collection practice for starting materials of herbal origin (e.g., European Medicines Evaluation Agency HMPWP/31/99). Upon receipt of the starting materials at a processing facility, it is the responsibility of the drug substance manufacturer to determine the suitability of these raw materials before use. This can be accomplished by examining and/or testing to ensure that the acceptance criteria are met and by documenting the quality control for the processing of the starting materials. FDA will review the inspection and examination of starting materials upon receipt when conducting a current good manufacturing practice (CGMP) inspection of a drug substance manufacturer.



Points to Consider on Good Agricultural and Collection Practice for Starting Materials of Herbal Origin: EMEA Working Party on Herbal Medicinal Products (HMPWP); EMEA/HMPWP/31/99 Rev 3 (Final release: May 2002)

Comment

Y N N/A


Quality Agreementso Agreements between producers and buyers of medicinal plants/herbal drugs with

regard to quality such as content of active principle, macroscopical and olfactory properties, limit values for microbial contamination, chemical residues and heavy metals, etc., must be based on recognized regional and/or national specifications and should be laid down in written form.

Personnel and Educationo All primary processing procedures should fully conform with regional and/or

national guidelines on food hygiene and personnel entrusted with handling of medicinal plants/herbal drugs should be required to have a high degree of personal hygiene (including personnel working in the field) and have received adequate training regarding their hygiene responsibilities.

o The welfare of all staff involved in growing and processing should be ensured.

o Personnel must be protected from contact with toxic or potentially allergenic medicinal plants/herbal drugs by means of adequate protective clothes.

o Persons suffering from known infectious diseases transmittable via food, including diarrhea, or being transmitters of such diseases, must be suspended from areas where they are in contact with medicinal plants/herbal drugs, according to regional and/or national regulations.

o Persons with open wounds, inflammations, and skin infections should be suspended from areas where the plant processing takes place or should have to wear appropriate protective clothing/gloves until their complete recuperation.

o Personnel should receive adequate botanical training before performing tasks that require this knowledge.

o Collectors must have sufficient knowledge of the plant they have to collect. This includes identification, characteristics and habitat requirements such as shade, humidity, soil, etc. The collectors must be able to differentiate between the collected species and botanically related and/or morphologically similar species to avoid any risk to public health. Collectors should have sufficient knowledge about the best time to harvest and harvesting technique and the importance of primary processing to guarantee the best possible quality.




Comment

Y N N/A


o If collectors are without sufficient knowledge, a local supervisor should guarantee the education, supervision, and documentation.

o It is advisable to educate all personnel dealing with the medicinal plant/herbal drug and all those engaged in its cultivation regarding cultivation techniques, including the appropriate use of herbicides and pesticides.

o Collectors of medicinal plants/herbal drugs should be instructed on all issues relevant to the protection of the environment and conservation of the plant species. This will include information on regulations related to protected species.

Building and Facilitieso Buildings used in the processing of harvested medicinal plants/herbal drugs must

be clean, as well as thoroughly aerated and must never be used for housing livestock.

o Buildings must provide adequate protection for the harvested medicinal plants/herbal drugs against birds, insects, rodents, and domestic animals. In all storage and processing areas suitable pest control measures such as baits and electric insect killing machines must be operated and maintained by professionally qualified staff or contractors.

o It is recommended that the packaged medicinal plants/herbal drugs be stored: (1) in buildings with concrete or similar easy to clean floors; (2) on pallets; (3) with a sufficient distance from the wall; and (4) well separated from other herbal drugs to avoid cross-contamination. Organic products must be stored separately.

o Buildings where plant processing is carried out must have changing facilities as well as toilets including hand washing facilities, according to regional and/or national regulations.

Equipmento Equipment used in plant cultivation and processing should:

Be clean, regularly serviced and oiled to ensure good working order and mounted, where applicable, in an easily accessible way. Furthermore, machinery used in fertilizer and pesticide application must be regularly calibrated.




Comment

Y N N/A


Those machine parts that are in direct contact with the harvested medicinal plants/herbal drugs must be cleaned after use to ensure that remaining residue does not result in subsequent cross contamination.

The equipment should be made from appropriate materials so that cross contamination of medicinal plants/herbal drugs with chemicals and other non-desirable substances is prevented.

Documentationo All processes and procedures that could affect the quality of the product must be

documented.

o Extraordinary circumstances during the growth period that may influence the chemical composition of the medicinal plants/herbal drugs such as extreme weather conditions and pests, particularly in the harvest period must be documented.

o For cultivated medicinal plants/herbal drugs all processing steps have to be documented, including the location of cultivation. Field records showing previous crops and plant protect products used should be maintained by all growers.

o For cultivated medicinal plants/herbal drugs, it is essential to document the type, quantity, and date of harvest, as well as the chemicals and other substances used during production such as fertilizers, pesticides, herbicides, and growth promoters.

o The application of fumigation agents must be documented.

o The geographic location of the collection area and harvest period should be described as precise as possible.

o All batches from each designated area should be unambiguously and unmistakably identified by batch number. Assignment of batch number should take place at an early stage. Collected and cultivated medicinal plants/herbal drugs material should carry different batch numbers.

o Batches from different geographical areas shall be mixed only if it can be guaranteed that the mixture itself will be homogeneous. Such processes should be well documented.




Comment

Y N N/A


o All agreements (production guidelines, contracts, etc.) between producer or collector and buyer should be in written form. It should be documented that cultivation, harvesting, and production have been performed in accordance with these agreements. Minimum information included in the documentation should cover geographical location, country of origin and responsible producer.

o The results of audits should be documented in an audit report (copies of all documents, audit reports, analysis reports, etc.) to be stored for a minimum of 10 years.

Seeds and Propagation Materialo Seeds should be verified botanically, indicating genus, species,

variety/cultivar/chemotype and origin should be traceable. The same applies to vegetatively propagated medicinal plants. Seeds and/or vegetatively propagated medicinal plants used in organic production have to be certified as organic. The starting material should be as free as possible from pests and diseases in order to guarantee healthy plant growth. Species resistant or tolerant to disease should preferably be used.

o The presence of different species, varieties or different plant parts has to be controlled during the entire production process, and such adulteration should be avoided. The use of genetically modified medicinal plants or seeds must comply with regional and/or national regulation.

Cultivationo Soil and fertilization

Medicinal plants should not be grown in soil contaminated with sludge, heavy metals, residues, plant protection products or other chemicals. Any chemicals used in the growth or protection of the crop should be kept to a minimum.

Manure applied should be thoroughly composted and should be void of human feces.

All other fertilizing agents should be applied sparingly and in accordance with the needs of the particular species. Fertilizers should be applied in such a manner as to minimize leaching.

o Irrigation Irrigation should be controlled and carried out according to

the needs of the medicinal plant.




Comment

Y N N/A


Water used in irrigation should comply with regional/national quality standards.

o Crop Maintenance and Plant Protection Tillage should be adapted to plant growth and requirements.

Pesticide and herbicide applications should be avoided as far as possible. When necessary, approved plant protection products should be applied at the minimum effective level in accordance with the recommendations from the manufacturer and authorities. The application should be carried out only by qualified staff using approved equipment. The minimum interval between such treatment and harvest time must be stipulated by the buyer or be consistent with recommendations from the manufacturer of the plant protection product. Regional and/or national regulations on maximum residue limits in the European Pharmacopoeia, European Directives, Codex Alimentarius etc. should be complied with.

Collectiono Individuals should be designated to identify and verify collected medicinal

plants/herbal drugs and to supervise collectors.

o Collection must be carried out in compliance with existing regional and/or national species conservation legislation. Collection methods must not damage the growth environment ensuring optimum conditions for regeneration of the medicinal plants/herbal drugs harvested.

o Medicinal plants/herbal drugs from species that are listed as endangered (CITES or Convention on International Trade in Endangered Species of Wild Fauna and Flora) must not be collected unless the relevant competent authority has given its authorization.

o The recommendations for quality assurance, buildings & facilities, equipment, and documentation must be followed.

Harvesto Medicinal plants/herbal drugs should be harvested when they are at the best

possible quality for the proposed use.

o Damaged plants or parts need to be excluded.




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o Medicinal plants/herbal drugs should be harvested under the best possible conditions avoiding wet soil, dew, rain, or exceptionally high air humidity. If harvesting occurs in wet conditions, possible adverse effects on the medicinal plant/herbal drug due to increased moisture levels should be counteracted.

o Cutting devices or harvesters must be adjusted such that contamination from soil particles is reduced to a minimum.

o The harvested medicinal plant/herbal drug should not come into direct contact with the soil. It must be promptly collected and transported in dry, clean conditions.

o During harvesting, care should be taken to ensure that no toxic weeks mix with the harvested medicinal plant/herbal drugs.

o All containers used during harvesting must be clean and free of contamination from previous harvests. When containers are not in use, they must be kept in dry conditions free of pests and inaccessible to mice, rodents, livestock, and domestic animals.

o Mechanical damage and compacting of the harvested medicinal plant/herbal drug that would result in undesirable quality changes must be avoided. In this respect, attention must be paid to overfilling of the sacks and stacking of the sacks.

o Freshly harvested medicinal plant/herbal drug must be delivered as quickly as possible to the processing facility in order to prevent thermal degradation.

o The harvested crop must be protected from pests, mice, rodents, livestock, and domestic animals. Any pest control measures must be documented.

Primary Processingo Primary processing includes washing, cutting before drying, fumigation, freezing,

distillation, drying, etc. All of these processes must conform to regional and/or national regulations.

o On arrival at the processing facility, the harvested medicinal plant/herbal drug has to be promptly unloaded and unpacked. Prior to processing, the material should not be exposed to direct sunlight, except in cases where there is a specific need; it must be protected from rainfall.




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o In the case of natural open air drying, the harvested medicinal plant/herbal drug must be spread out in a thin layer. In order to secure adequate air circulation, the drying frames must be located at a sufficient distance from the ground. Drying directly on the ground or under direct exposure to sunlight should be avoided unless specifically required. Attempts must be made to achieve uniform drying of the harvested medicinal plant/herbal drug and thus, avoid mold formation.

o Except in the case of open air drying, the drying conditions (e.g., temperature, duration, etc.) must be selected, taking into consideration the medicinal plant part such as root, leaf, or flower and the nature of its active constituent such as essential oils. The source of heat in direct drying should be limited to butane, propane, or natural gas. Individual conditions must be recorded in detail.

o All materials must be inspected and, where necessary, sieved in order to eliminate sub-standard product and foreign bodies. Sieves must be maintained in a clean state and should be serviced regularly.

o Clearly marked waste bins should be available, emptied daily and cleaned.

Packagingo In order to protect the product and to reduce the risk of pest attacks, early

packaging is advisable.

o Following processing monitored by in process controls, the product should be packaged in clean and dry, preferably new sacks, bags, or cases. The label must be clear, permanently fixed and made from non-toxic material. Information must conform with regional and/or national labeling regulations.

o Reusable packaging material should be well cleaned and perfectly dried prior to use. No contamination should occur through reuse of bags.

o Packaging materials must be stored in a clean and dry place that is free of pests and inaccessible to livestock and domestic animals. It must be guaranteed that no contamination of the product occurs by use of packaging materials, particularly fiber bags.

Storage and Distribution




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o Packaged dried medicinal plant/herbal drugs, including essential oils, should be stored in a dry, well aerated building, in which daily temperature fluctuations are limited and good aeration is ensured. Fresh products should be stored between 1°C and 5°C while frozen products should be stored below -18°C (or below -20°C for long term storage).

o In the case of bulk transport, it is important to secured dry conditions. Furthermore, in order to reduce the risk of mold formation or fermentation, it is advisable to use aerated containers. As a substitute, the use of sufficiently aerated transport vehicles and other aerated facilities is recommended. Essential oil transport must conform with appropriate regulations. Regional and/or national regulations on transport have to be respected.

o Fumigation against pest attack should be carried out only where necessary and must be performed by licensed or trained personnel. Only registered chemicals can be used. Any fumigation should be reported in the documentation.

o For fumigation of warehouses, only substances permitted by the regional and/or national regulations should be used.

o When frozen or saturated steam is used for pest control, the humidity of the material must be controlled after treatment.


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