Questions & answers on the Australian code of good manufacturing practice for medicinal products
Version 7, October 2004
Note:
- The 2002 Australian Code of GMP refers to the Australian Code of Good Manufacturing Practice for Medicinal Products, 16 August 2002 <http://www.tga.gov.au/docs/html/gmpcodau.htm>.
- Unless otherwise specified, clauses and Annexes referred to in this document are those of the 2002 Australian Code of GMP.
- The 1990 Australian Code of GMP refers to the Australian Code of GMP for Therapeutic Goods - Medicinal Products, August 1990.
Quality management (Chapter 1)
1. What is "marketing authorisation"?
Marketing authorisation is a set of regulatory requirements specified on the ARTG and any other requirements imposed by a relevant Delegate of Secretary upon product listing or registration.
Examples of regulatory requirements include, but not be limited to, compliance with registered formulations, special storage and transportation conditions, shelf life, labelling, batch release testing requirements etc.
2. What is TGA's expectation during audit in relation to marketing authorisation (regulatory compliance) of products?
The person releasing goods for supply must ensure that products meet regulatory requirements. Final release must include assurance of compliance with marketing authorisation, regardless of who carries out the release for supply. This applies to both local and overseas manufacturers.
3. Regarding audits of marketing authorisation against ARTG details, does this refer to only products manufactured at the site of audit, products manufactured by a third party, imported products, or all products?
It refers to products manufactured by the company being audited, irrespective of whether the products are the company's own products (ie. the manufacturer is the sponsor) or whether the products are manufactured under contract, if the company is responsible for release for supply. This applies to Australian and overseas manufacturers.
Where an overseas manufacturer is certified by another regulatory authority as being in compliance with the PIC/S or EU GMP requirements, it will be presumed that the manufacturer complies with the requirement for ensuring that the marketing authorisations for all products manufactured are complied with.
4. Is the holder of the Marketing Authorisation the product sponsor? Is the ARTG going to adopt this term?
The holder of the Marketing Authorisation is the sponsor. The ARTG will not be adopting this term as it is equivalent to a Certificate of Registration or a Certificate of Listing for a medicinal product under Australia's Therapeutic Goods Act 1989.
5. Do distribution records require batch numbers?
The interpretation of Clauses 1.3(vii) and 8.12 is that the recording of batch numbers in distribution records is mandatory.
Personnel (Chapter 2)
6. What does 'necessary qualifications' mean in clause 2.1?
In the absence of a definition in the 2002 Australian Code of GMP, the TGA will continue to reference the meaning as specified in clauses 301 and 305 of the1990 Australian Code of GMP. In the absence of relevant formal qualifications the company will be requested to provide justification based on risk, noting the nature of the product and complexity of the operation. Clauses 301 and 305 of the 1990 Australian Code of GMP are provided below:
Australian Code of GMP, 1990:
301 Personnel should have the education, training, experience and skills or any combination of these elements that will ensure that they can perform assigned duties and functions at an acceptable level.
305 The persons in charge of production and of quality assurance respectively should usually have studied a relevant science (e.g. pharmacy, chemistry, chemical engineering, microbiology, food technology) at university or technical institute level and have had practical experience under professional guidance in the manufacture and control of therapeutic goods made under GMP. They should be different persons, neither of whom is responsible to the other unless other arrangements acceptable to the inspecting authority are made, yet each should have a responsibility for the achievement of product quality.
7. What are training requirements for personnel (clauses 2.8-2.12)?
It is expected that training be carried out by persons with relevant training, qualifications and experience in the subject matter and should preferably be themselves trained as trainers.
Training (and records thereof) should be given to people affected in all circumstances where significant change occurs in the quality management system, eg when SOPs or methods are changed. This requirement should be reflected in procedures.
There are a number of people who have a direct bearing on quality outcomes. These include contractors, consultants and casual employees. Appropriate training should be provided.
8. What are language requirements for personnel?
Manufacturers should define language requirements or standards and ensure personnel are proficient in regard that language for their allocated tasks, particularly in relation to documenting and recording. Procedures employed to overcome identifiable deficiencies should be documented.
Premises and equipment (Chapter 3)
9. What environment (including air supply) is required for sampling of starting materials?
Clause 3.9 describes the physical requirements for the area being used to sample starting materials. Sampling of starting materials should be carried out in a separate room, or appropriately qualified sampling hood, under a filtered air supply to protect product from contamination. The sampling area should be designed with dust extraction or equivalent controls to prevent contamination of adjacent areas.
Sampling hoods can be used provided there is no possibility of contaminating the storage area and that the hood has appropriate filtering/de-dusting facilities, has been qualified and that materials sampled are not high risk.
10. What environment is required for sampling primary packaging materials? Can they be sampled in the warehouse?
Clause 3.9 also describes the physical requirements for the area being used to sample primary packaging materials. The standard of air quality is optional and HVAC is not expected. However, sampling in an open warehouse would not be allowed.
11. What is the definition of 'campaign' manufacture? How may this be utilised, ie what are the requirements?
Clause 5.19 defines campaign manufacture as being a separation in time of production. That is, manufacturing a series of batches of the same product in sequence in a given period of time and/or maximum number of batches followed by an appropriate (validated) cleaning procedure. Clause 5.19 provides an example of how it may be utilised.
12. The new Code does not reference a specific standard for air quality for non-sterile manufacturing areas. Could you please advise the relevant Australian or ISO standard, and the correct area designations and standards we should apply?
There are no standards specific to non-sterile medicine manufacture. The various grades of air quality for the production of non-sterile medicines will require further consultation with industry before a TGA policy is issued on this topic.
13. What does 'certain' (as per certain additional products, certain antibiotics, certain hormones etc) in clause 3.6 of the 2002 Australian Code of GMP mean?
In the absence of a specific definition in the 2002 Australian Code, the TGA will interpret the term 'certain' as per clauses 627-633 of the 1990 Australian Code of GMP.
Australian Code of GMP, 1990:
627 Penicillins should be produced only in separate buildings, with separate air handling facilities, dedicated to these products and preferably on separated sites, except where the inspecting authority accepts a totally segregated internal unit with an adequate residue testing program.
However, penicillin products may be relabelled on dedicated equipment or by campaign packaging in segregated areas using validated cleandown procedures.
628 Cephalosporins should be produced in segregated areas using dedicated equipment, including dedicated packaging lines or by campaign manufacture in segregated areas using validated cleandown procedures. Particular care should be taken to prevent contamination with penicillins.
However, cephalosporins may be relabelled under the conditions specified in Clause 629.
629 Cross-contamination of products by live biologicals, or by drugs such as certain steroids or antineoplastics which in trace amounts may produce physiological effects should be prevented by methods such as:
- carrying out manufacturing operations in separate buildings or adequately isolating the operations by total enclosure or making successive batches in the same or in dedicated equipment followed by intensive cleaning and where appropriate, fumigation;
- controlling airborne contaminants by the use of an appropriate air pressure differential in processing areas or adequate exhaust systems and filters, together with control of recirculated air;
- the siting and shielding of manufacturing equipment, and wherever possible the use of equipment used solely for the one drug;
- containment of contaminant-transfer by means of air-locks, clothing change and the decontamination of containers and other articles prior to their removal from the isolated area;
- separate cleaning of contaminated clothing;
- periodic testing of the environment around the manufacturing areas for the presence of the therapeutic substance being processed; and;
- validation of cleaning procedures.
630 Air handling facilities for the manufacture of antineoplastic drugs should be in accordance with the principles for air handling given in Australian Standard 2639-1983: Cytotoxic Drug Safety Cabinets - Installation and Use. Where the manufacture involves handling only a few grams of active substance, the option of operating at positive pressure, with the anteroom at higher pressure is appropriate: for larger quantities, the option of operating at negative pressure (again with the anteroom relatively higher pressure) is appropriate.
Notes:
(1) The requirements of the Standard relating specifically to sterility may not be applicable to products not intended for parenteral administration. However, for sterile products the requirements of the Standard are additional to those of Part 2 of this Code (1990 Code).
(2) The negative pressure mode is under review.
631 Filters in hoods and air handling systems should be serviced or replaced by specially trained personnel, following a standard operating procedure.
632 A standard operating procedure should be written to specify the procedures to be adopted if spillage occurs. Operators should be trained in these procedures.
633 Standard operating procedures for the safe storage and disposal of waste material should be enforced.
14. The 2002 Australian Code of GMP appears to contain very little detail on requirements for cleaning and sanitisation. What will the TGA consider to be an acceptable standard for these requirements?
In the absence of a clear direction from the 2002 Australian Code of GMP, the TGA will continue to use clauses 403, 404, 405, 406, 407, 409 and 410 of the 1990 Australian Code of GMP as a guide.
Australian Code of GMP, 1990:
403 A written cleaning and, where necessary, sanitation procedure should be established for all production areas and stores. Relevant sections should be readily available to staff and should specify, as appropriate:
- the area to be cleaned;
- the frequency (and where necessary, to times) of cleaning'
- the steps to be taken;
- the responsibilities for cleaning operations;
- the materials (e.g. detergent, disinfectant) and equipment to be used;
- methods for the cleaning, decontamination, drying and storage of mops, brushes and other cleaning equipment;
- special precautions necessary in particular areas, e.g. wash-up areas or where appropriate, fan blades; and
- record keeping.
404 Written procedures should be established and available for cleaning and, where necessary, sanitising all equipment. Operators should be familiar with these procedures, which should include:
- the responsibility for cleaning;
- whether re-cleaning or sanitising is necessary before next use and the procedures that ensure that these steps have occurred;
- materials and equipment to be used;
- extent of disassembly;
- all necessary steps, including rinsing, drying and (preferably) covering and storage;
- procedures for cleaning hoses and associated fittings;
- documentation (tags, logs); and
- special precautions, where applicable.
405 Cleaning equipment or material that shed particles, raise dust, produce aerosols or otherwise generate contamination should be avoided where possible. These include compressed air, bristle brushes, fibre-shedding cloths and certain designs of floor-scrubbing machines. Vacuum or wet cleaning methods are preferred. Vacuum cleaners or polishers should be fitted with fine dust filters.
406 Instructions describing the correct storage and use of disinfectants should emphasise:
- ensuing that objects and surfaces to be treated are pre-cleaned;
- disassembly of equipment being treated;
- using only the specified disinfectants;
- the dilution of each disinfectant and the correct choice of diluent; and
- avoiding further dilution or storage or 'topping up' during use but, where storage is not avoidable, labelling any stored dilution with an expiry date.
If contamination of finished products or colonisation of equipment or the environment with pathogens or potential pathogens is discovered, the choice of disinfectant and the conditions of its use should be carefully reviewed by Quality Assurance in connection with an investigation of the origin(s) of the contamination.
407 If wet areas or open drains are present in production areas, there should be specific procedures for their cleaning and decontamination.
409 A system should be in operation which ensures that cleaning and, where necessary, sanitising has occurred after use and, where necessary, before re-use of equipment.
Where equipment is dedicated to one formulation only or used for a run of batches of the same formulation, cleaning should remove as much as practicable of each batch before proceeding to the next. In such cases, the maximum period or maximum number of batches that are permitted to elapse before complete cleaning must be carried out should be specified in a standard procedure which should be supported by validating data.
410 Except where a specific program has been written for or a single written instruction issued to an external contractor, the manufacturer's cleaning and sanitation program should be used, in manufacturing areas, by all employees and all contractors.
15. Is a facility that is used as a warehouse and distribution centre AFTER release of a pharmaceutical product, required to meet GMP?
By definition, "manufacture" includes all steps in bringing the product to its final form and "release for supply" is considered to be the last step in this process. From a GMP point of view, this means that warehousing/distribution after release for supply is not regulated by the TGA and a licence to manufacture therapeutic goods is not required. There may be State requirements that you will have to comply with and you should check this with your State Department of Health.
Documentation (Chapter 4)
16. In the 2002 Code, 4.17 (b) references recording the date and 'time' of commencement of significant intermediate stages, and of completion of production. If we utilise equipment with built in timer controls (eg. blenders and granulators) that are calibrated and checked, do we need to record the time this operation occurred, as we have assurance that the operation was conducted for the correct time period?
The use of in-built timers measuring specific processing activities, eg. mixing times, will not satisfy clause 4.17(b) (this clause relates to the entire processing cycle) as distinct from the permitted duration of (time) critical sub-processing steps as measured and controlled by (eg.) a 'built-in timer'.
Production (Chapter 5)
17. The Batch Coding Requirements appear less onerous in PIC/S Code. The 1990 Australian Code required batch number to not only designate a batch, but also the product, ie totally unique. It seems to be current EU practice, (and implied by PIC/S Code), that combination of product SKU and batch code only needs to be unique, ie same batch number is acceptable for different SKUs.
It is acknowledged that the glossary of the new Code of GMP provides much less detail on batch numbering than the glossary of the old Code. However, the intention remains the same.
The issue of batch numbering is also dealt with in Therapeutic Goods Order No. 69 General Requirements for Labels for Medicines <http://www.tga.gov.au/docs/html/tgo/tgo69.htm>. The system that a manufacturer adopts for batch numbering may include numerals, letters or symbols (or any combination of these) and must effectively serve to uniquely identify a batch of product and from which it is possible to trace that batch through all stages of manufacture and distribution. The manufacturer should be able to demonstrate that the system that they have established meets these requirements and is effective.
It is not possible to cover all situations in this answer however, under certain circumstances the use of a simple numeric batch number (eg 001, 002, -> 999) for different products which are otherwise easily distinguished may be acceptable.
For example:
| Product A (Red capsules) |
Product B (Blue capsules) |
|
|---|---|---|
| First batch | 001 | 001 |
| Second batch | 002 | 002 |
| Third batch | 003 | 003 |
18. What are the requirements for label counting and verification?
Roll labels must be counted either on receipt or at issue. Supplier counts are not acceptable unless the supplier is specifically qualified and supplier certifies the exact count for each roll. Supplier numbering of labels is an acceptable alternative.
Cut labels must be counted and effectively verified by the manufacturer because of risks of mix-up.
19. The current Australian Code of GMP appears to have no similar requirement to section 680 of the 1990 Australian Code of GMP which referred to an artwork revision code. This being the case, is there still an expectation that labels etc should bear such a code?
It is correct that the current Australian Code of GMP does NOT include the requirement for the artwork revision code, as was previously required under the Australian Code of GMP, 1990. Nonetheless, it is in a manufacturer's interests to (still) consider both the increased control and related benefits of (continuing to) do this. For example, clause 4.16 e) requires a manufacturer to provide "......an example or reproduction of the relevant printed packaging materials.....". In the past, manufactures have addressed (the equivalent of) this requirement by including the above referenced revision code, in the Bill of Materials and/or by on-line-verification.
Note however that the specific requirement for a revision code to appear in the text is no longer a mandated requirement, and therefore cannot appear as a deficiency in an audit report.
Quality control (Chapter 6)
20. Is it necessary to conduct stability studies at a GMP certified laboratory?
No. Stabitity testing is not a step of manufacture as defined in the Australian Therapeutic Goods Act. It is not "producing the goods" or "engaging in any part of the process of producing the goods".
21. A sponsor contracts the manufacturer of a listed product. The GMP agreement says that the sponsor accepts the responsibility for stability. There is NO stability in the listing (marketing authorisation). How can the manufacturer be held responsible for stability?
There will be further consultation with representatives of the complementary medicines industry on this topic in relation to listed medicinal products.
22. If the stability now is the responsibility of the Manufacturer. To a contract Manufacturer. For such responsibility can be clearly stated in an agreement between the sponsor and the Manufacturer, like the old Code says? Is the Manufacturer still able to produce products that the stability has not been done?
The company carrying out the Release for Supply step would need to ensure that the batch meets its Marketing Authorisation.
23. BP specifies Conductivity Testing for WFI for Manufacturing with a limit of 1.1 microsiemens/cm. How can this be achieved with the non-availability of accurate conductivity equipment at this level of 1 microsiemens/cm? The difficulty to calibrate the instrument at this level is also difficult.
Equipment to measure conductivity at these levels is available and can be appropriately calibrated.
24. The TGA 1990 Code referenced the Australian Standard for setting the standard for GLP. What standard will apply now?
Australian Standard 2830.1 is referenced in the old Code as a GLP standard. This standard is no longer applicable.
Although the new Code does not reference or mandate any specific GLP requirement, the ISO Standard ISO/IEC/EN 17025-1999 (formerly ISO Guide 25 & EN45001) entitled 'General Requirements for the Competence of Calibration and Testing Laboratories' provides useful guidance for QC laboratories involved in the testing of medicinal products.
Contract manufacture and analysis (Chapter 7)
25. Is there a guideline for contract manufacture?
The TGA does not have a specific guideline for contract manufacture. However, the Australian Self-Medication Industry has developed a document Guideline for Pharmaceutical Contract Manufacture, which is available from the ASMI website <http://www.asmi.com.au>.
Manufacture of sterile medicinal products (Annex 1)
26. Where do isolators fit with manufacturing of penicillin and other drugs with compounding the one room? NB specifically negative pressure containment isolators for closed system preparations. Are the isolators, with their dedicated air handling system, considered separate?
It is generally accepted by European regulatory authorities that dedicated buildings, facilities and equipment are required for penicillin manufacture. An isolator operating at negative pressure would be regarded as a 'micro-environment' and could be accepted for penicillin manufacture provided that factors such as cleaning, sanitation (noting that if the isolator is opened during cleaning this could present specific concerns), preventative maintenance, environmental monitoring (residues), spillage, etc. are adequately addressed with respect to cross contamination. However, the manufacture of 'other drugs' in the isolator used for penicillin would not be permitted.
27. Where in the GMP does clean room apparel fit in? Can they be licensed as a manufacturer of starting material?
Clean room apparel is not a therapeutic good and manufacturers of such goods are not subject to audit and licensing under the Therapeutic Goods Act 1989. However, licensed manufacturers of sterile medicinal products should qualify their vendors of critical goods such as clean room apparel under their quality management system.
Manufacture of biological medicinal products (Annex 2)
28. Does the scope of Annex 2 include such things as beta-carotene as extracted from kelp and some of the antibiotics eg Gentamicin, Tobramycin?
As a general guide, the following are considered biological medicinal products under the requirements of Annex 2:
- Animal derived fractionation products
- Antibiotics produced by fermentation
- Antigens
- Antitoxins, antivenenes, enzymes and venoms
- Allergenic products
- Biological therapeutics products
- Cytokines
- Hormones
- Human derived fractionation products
- Immunosera
- Monoclonal antibodies
- Somatic cellular products
- Therapeutic recombinant products
- Toxoids/toxins
Also, as a general guide, although the following could be considered biological medicinal products, the additional requirements of Annex 2 will not be applied:
- Beta-carotene
- Shark cartilage
- Bee propolis
- Green lipped mussel
- Deer antler
29. Please clarify: rDNA products (API manufacture) listed on slide as falling under Annex 2 rather than Q7A API GMP Guide - ie. does API manufacturers of rDNA product need to follow Annex 2?
Annex 2 relates to the manufacture of biological medicinal products for human use. If a material is classified as an API in Australia (if it is manufactured in Australia or used in a medicinal product in Australia), it should be manufactured according to the requirements of the ICH Harmonised Tripartite Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients <http://www.tga.gov.au/legis/mp0201.htm>. The ICH Guide excludes vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation) and gene therapy APIs, and the sterilisation and aseptic processing of sterile APIs. Any specific concerns regarding the interface between the API and the finished product may be discussed with the TGA.
Manufacture of herbal medicinal products (Annex 7)
30. Define 'authenticated reference herb'. Is the TGA going to supply the industry with: a) list of names of where authenticated herbs can be purchased, b) methods so that the industry can obtain accurate results?
An 'authenticated reference herb' is no different than any other standard reference substance used in QC analysis. The CHC (Complementary Healthcare Council of Australia) is in the process of developing a list of suppliers of authenticated reference herb and test methods.
31. If a company has identified actives or 'marker compounds' in herbal products but there are no commercially available primary standards, how are they to conduct assays (HPLC) in a production environment and still satisfy the Code?
If a company selects 'x' as a marker compound, they should obtain a suitable reference material of 'x' from external or internal sources.
32. Does the TGA interpret 'quantified at input' to be equivalent to 'Standardized to contain' in the context of active claims on herbal medicines?
Please refer to Guide to interpretation of the Australian Code of Good Manufacturing Practice for Medicinal Products (16 August 2002) applicable to the manufacture of complementary medicines on this website <http://www.tga.gov.au/manuf/gmpcodau_cm.htm>.
33. Will 'quantified on addition' be no longer allowed on Certificates of Analysis?
Please refer to Guide to interpretation of the Australian Code of Good Manufacturing Practice for Medicinal Products (16 August 2002) applicable to the manufacture of complementary medicines on this website <http://www.tga.gov.au/manuf/gmpcodau_cm.htm>.
Sampling of starting and packaging materials (Annex 8)
34. What constitutes a validated procedure that would permit less than all containers to be sampled and tested for identification purposes?
- Every container of starting material must be identified if the supplier is not classified as reliable and is not validated according to Annex 8.
- Requirements for sampling active materials do not differ from those for excipients.
- The validation of a supplier cannot be accepted without a regular and adequate audit. Requirements applied to supplier evaluation are as per those required by European regulatory authorities; such evaluation should comprise a number of actions, which may include all or most of the following:
- The use of a questionnaire prepared by the potential customer and completed by the potential supplier, concerning the supplier's operating Quality System.
- Approval audit of the potential supplier's operation by the potential customer, or by a third party on their behalf. For example, a sister company located in the same country as the supplier. Reliance on audit reports of other regulatory authorities by the potential customer is normally not sufficient, unless it can be demonstrated and that the audit covered the specific operations to be used in the processing of materials for the potential customer.
- A program to evaluate the quality of each shipment of materials on receipt by the customer. In this regard, sampling of powders should be representative of the container contents. For example, sampling from the top, middle and bottom of drums, in the absence of validated sampling positions. Reduced testing programs should be evaluated by the auditor. Sampling by the suppliers should be validated.
- A program for regular re-audit of the supplier's operation and for ongoing monitoring of the quality of material supplied, for example, through trend analysis of analytical results, periodic full testing.
- In the case of active ingredients, the use of brokers as sources should be carefully evaluated. The quality of each batch of material should be confirmed through testing of representative samples.
- Certification eg a Certificate of Suitability of Monographs of the European Pharmacopoeia does not replace an audit.
35. What would be an acceptable method to validate sampling of starting material if vn+1 is to be used?
The above answer provides guidance on the establishment of a validated procedure to justify reduced sampling. It follows that where scientific and statistical evidence is presented, vn+1 sampling may as applicable be justified.
36. How will the TGA interpret compliance with the requirement to sample every bag of starting materials indicated in Annex 8? For example, if suppliers are certified and regularly audited by a company, is it necessary to sample and test every bag of every delivery.
Sampling of every container may not be necessary if appropriate validation is done as outlined in an answer above.
Note, however, that the Code indicates that "it is improbable that a (sampling) procedure could be satisfactorily validated for starting materials supplied by intermediates such as brokers where the source of manufacture is unknown or not audited, and for starting materials for use in parenteral products".
Computerised systems (Annex 11)
37. When the PIC/S computer validation document is finalised, will it be mandated?
As this document is not adopted as a Manufacturing Principle in Australia, it is not a mandated requirement. However, the various guidance contained in the document does provide a means of meeting the requirements of Annex 11 of the new Code.
Use of ionising radiation in the manufacture of medicinal products (Annex 12)
38. What are the parts of the 2002 Australian Code relevant to the use of radiation in the manufacture of medicinal products?
The 2002 Australian Code Annex 12 gives specific requirements for use of ionising radiation. In medicinal product manufacture ionising radiation is primarily used for bioburden reduction/sterilisation but could be used for other purposes (eg alteration of a molecule to make it pharmaceutically active). The Annex deals specifically with Gamma and Electron Beam radiation.
Radiopharmaceuticals are covered by Annex 3.
Items 70-75 of Annex 1 are specific requirements for sterilisation.
Annex 12 is particularly relevant and the items listed in this Annex are self-explanatory.
Manufacture of investigational medicinal products (Annex 13)
39. How does Annex 13 distinguish between earlier and late phase clinical trials in requirements for drug product stability and characterisation studies (including level of assay validation required)?
The manufacture of Phase 1 clinical trial medicines is not subject to audit and licensing by the TGA (specified in item 1, schedule 7, Therapeutic Goods Regulations). However the manufacture of Phase 2 and 3 clinical trial products is subject to audit (including Annex 13) and licensing by the TGA.
There are currently no moves to change this regulation.
40. We have a dedicated pilot plant for the development of dosage forms and new products. This area operates to a similar standard as our normal manufacturing area (air quality, SOPs, GMP, GLP, etc.). This area is not used for the manufacture of saleable product. Under the new Code, will the TGA inspect this area? It is not mentioned on any of our current licences. Do we need to be licensed for the manufacture of investigational medicinal products?
The dedicated pilot plant would not need to be audited or licensed unless medicinal products to be used in Phase 2 or Phase 3 clinical trials were manufactured in that plant.
Qualification and validation (Annex 15)
41. How relevant is PIC/S document Validation Master Plan Installation and Operational Qualification Non-Sterile Process Validation Cleaning Validation to the 2002 Australian Code of GMP?
The TGA encourages the use of this document as it expands on clauses 5.21, 5.22, 5.23, 5.24 and Annex 15 of the 2002 Australian Code of GMP.
Note also that although there are less detailed requirements in the 1990 Australian Code of GMP, the 2002 Australian Code of GMP requires that processes be validated for reproducability and consistency. Manufacturers are required to provide evidence that validation of processes has been carried out according to Annex 15 requirements and that process conditions established during validation are in agreement with marketing authorisation and have been demonstrated to 'yield a product consistently of the required quality'.
42. Is it necessary to revalidate an already established and previously validated process?
Validation is required to ensure that product consistently meets product specifications and this principle is to be applied for all products (including complementary medicines). There are some critical processes that must be validated and risk assessment wouldn't be able to justify exemption from validation (eg. mixing for tablets/capsule/powder dosage forms). For herbal products grouping can be considered and justification included in the VMP. Markers can be used for herbal process validation.
Clause 45 of Annex 15 is quite specific on the issue of revalidation, ie. 'Facilities systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation'.
The frequency of periodic revalidation is intentionally not defined (except for example, sterile media trials under Annex 1, clause 44) because this will vary according to a large range of factors. Manufacturers need to determine and justify their own revalidation frequency based on a risk assessment and other relevant factors.
If the process has not been previously validated, then it should be validated retrospectively according to items 31-35 of Annex 15. When retrospective validation is inadequate, then validation according to Annex 15 is required. The scope and extent of validation should be based on risk assessment and should be conducted according to a validation master plan.
43. Should batches made for process validation be the same size as the intended industrial scale batches?
The process must be validated for the smallest and the largest batch sizes. There may be no need to carry out process validation for intermediate batch sizes if it could be demonstrated, based on risk assessment, that process consistency can be achieved for any intermediate batch size.
44. Should the scope and extent of validation be based on risk analysis?
Yes, risk assessment approach to validation should be applied. Identification of qualification and validation work is required to prove control of the critical aspects of the particular operation. Commonsense approach should be applied.
Is performance qualification (PQ) required to be carried out for each item of critical process equipment, if we are going to carry out a process validation exercise on the same equipment? Some people say, if you are carrying our process validation exercise, then you are also covering the performance parameters of the equipment.
Yes, for significant changes to equipment (eg. for new or modified items of equipment), equipment qualification is separate from and precedes, process validation.
No, for changes not impacting on already qualified equipment (eg. to processing parameters only), then arguably process validation would not need to be preceded by qualification.
Auditing and licensing
45. TGA File Notes forwarded to manufacturer post audit - will the manufacturers be given the opportunity to comment or seek clarifications on the File Notes?
The system of recording information about the manufacturer in a 'GMPALS File Note' is no longer used by the TGA. Instead, the European inspection report format is being used whereby a brief description of the companies operations and procedures noted during the audit and any deficiencies are recorded in the one audit report. This is the approach and format used by all PIC/S Inspectorates.
The audit report will be sent to the manufacturer.
46. Does the addition of the word 'demonstrated' to the existing interpretation of the Code imply experimental proof on every point, or will scientific argument, or published data, or collective industry experience suffice? If it is 'experimental proof', is this because of arguments (based on opinion) that TGA auditors have lost?
Evidence or proof should always begin with good science and a sound technical position.
47. Will the changes in the Code and in the 'audit approach' for medicinal products affect the expectations and audit approach in relation to GMP inspection of in vitro diagnostics manufacture?
In vitro diagnostics are 'therapeutic devices' and therefore not subject to the requirements of the new Australian Code of GMP for Medicinal Products.
48. Will the Australian Pesticides and Veterinary Medicines Authority (AVPMA, formerly NRA) still accept TGA audits as applicable for veterinary manufacture where a company manufactures both medicines and veterinary products?
Yes, the TGA will cover veterinary medicinal products during TGA audits but such coverage needs to be requested before the audit takes place so the TGA auditor can allocate additional time for this work.
49. In the light of the new audit reporting procedure, what is the timetable for issue of a new/renewal GMP licence/certificate? Please cover duration of Certificate with respect to audit frequency.
Auditing of new licence applicants are given priority. Once a licence is issued it is not renewed unless a request is made for an amendment, eg. new conditions or new responsible persons nominated.
GMP certificates are issued with a 3-year expiry period which is not linked to the re-audit frequency; a re-audit could take place at any time during the 3-year life of the GMP certificate, depending on various risk factors associated with the manufacturer and the type of products manufactured.
Active pharmaceutical ingredients
50. Separate facilities for handling live micro-organisms - API manufacture for biopharm chemical, involves live organisms (closed system). Does finished product manufacture require separate facility if manufacturer produces both API and Drug products?
Closed systems provide a higher level of assurance than open systems.
Mutual recognition agreements
51. Australian new GMP Code has not adopted Annex 16 of PIC/S, how or what impact does this have on MRA between Australia and EU given the differences in 'qualified' and 'authorised' persons, definitions and associated responsibilities?
This will have no impact on the MRA between Australia and EU.
52. If you are a veterinary manufacturer audited by the TGA under the EU MRA, what role will Annexes 4 and 5 play? As these are deleted, what will the TGA reference to?
If the TGA is requested to audit a veterinary product manufacturer for the purpose of obtaining an 'MRA certificate' to enable that product to be exported to Europe, the TGA will use Annexes 4 and 5 of the EU GMP Guide, as well as other relevant parts and Annexes of the new Australian Code of GMP.
Imports
53. Please provide a brief summary of requirements for US manufactured drugs in light of the new GMP requirements.
The TGA will continue to accept the results of FDA inspections in USA. The TGA will also continue to accept results of inspections carried out on US manufacturers by EMEA or Australia's MRA partners. However, because Australia does not have an MRA with USA, the TGA reserves the right to conduct its own inspections of US manufacturers, particularly for herbal & vitamin preparations (which are not audited by FDA to medicine GMP requirements).
54. What are the implications of the new Code on products being imported into Australia?
There will be minimal change, as the TGA will continue to recognise GMP certificates and other evidence of GMP compliance as outlined in the Guidelines on Standard of Overseas Manufacturers. However, overseas audits done by the TGA are now to the new Australian Code of GMP for Medicinal Products.
Wholesale
55. Is the Code of GWP (Good Wholesaling Practice) issued by the TGA going to change as well in connection to the new GMP Code? If yes, when is it most likely to happen?
The Australian Code of GWP <http://www.tga.gov.au/docs/html/gmpgwp.htm> will not change as a result of the introduction of the new Code of GMP for Medicinal Products. The State and Territory Heath authorities are responsible for the inspection and licensing of wholesalers in their respective states and territories. The Therapeutic Goods Committee is reviewing the Code of GWP.
General
56. Can the expiration date on certificates given to overseas manufacturers, following a TGA audit, be lengthened considerably, so these certificates will not expire before and follow up audit takes place as imminent expiry causes considerable uncertainty to these manufacturers who do not know if they can continue to supply products unless re-audited?
GMP certificates are given a 3 year expiry date. This is not linked to the re-audit frequency which is often shorter than 3 years, depending on the types of products manufactured and other risk factors. If the TGA has not scheduled a re-audit of the manufacturer prior to the end of the 3-year expiry date, an extension of the expiry date can be arranged by the TGA provided the local sponsor agrees in writing to a re-audit by the TGA. A new GMP certificate cannot be issued until the re-audit has taken place and acceptable GMP compliance confirmed.
57. What is the fate of Appendix D of the 1990 Australian Code of GMP? Will the TGA still be using this as a reference or some other document?
Appendix D on Laboratory instrumentation was withdrawn by the TGA a number of years ago and is no longer referenced by TGA auditors. The BP/EP and other pharmacopoeias provide useful guidance on laboratory instrumentation.
58. Will the Site Master File format change with the New Code?
The format of the Site Master File <http://www.tga.gov.au/docs/html/siteinfo.htm> will remain unchanged, i.e. identical to that published by PIC/S and issued by the TGA in April 2000.
59. The 2002 Australian Code of GMP appears to contain very little information on requirements for handling product residues. What will the TGA consider to be an acceptable standard for these requirements?
In the absence of clear direction from the 2002 Australian Code, the TGA will continue to use clause 671 of the1990 Australian Code of GMP as a guide.
Australian Code of GMP, 1990:
671 Production residues should not be incorporated into subsequent batches of product on a routine basis except where this is provided for in the master formula or processing instructions and where limits are prescribed for the proportion of residue. In addition, a standard operating procedure should specify at least:
- limits on the age and total quantity of residue that may be accumulated;
- limits on the number of batches of residue that may be incorporated in a single batch of product;
- limits on the total quantity or proportion of residue that may be incorporated in a single batch of product;
- a procedure for utilisation and/or disposal that will facilitate overall reconciliation; and
- any necessary testing or approval, for example where dissolution rate may be affected or is required in relation to registration.
If you have questions that have not already been answered in the above set of Questions and Answers, you may wish to email the questions to the Manufacturer Assessment Section at gmp@tga.gov.au. Thank you for your interest.