Questions & answers on the code of good manufacturing practice for medicinal products

4 June 2013
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General issues

1. Why is the Code of GMP changing from time to time?

The TGA uses internationally harmonised manufacturing standards to allow manufacturers to operate in an international environment. The TGA maintains its GMP standards in line with updates issued through the PIC/S. Regular updates are necessary to maintain mutual confidence with regulators overseas and to promote quality assurance of inspections and harmonisation of technical standards and procedures with international inspection standards for the production and testing of medicinal products.

Australian manufacturers benefit from reduced regulatory burden where the TGA is able to adopt harmonised international standards and establish mutual recognition agreements and cooperation arrangements with comparable overseas regulatory authorities.

2. When did the current Code of GMP become mandatory?

The current Code of GMP was introduced on 29 July 2009 with a transition period up to 30 June 2010. It became mandatory from 1 July 2010.

3. What are the main new requirements introduced by the 2009 Code?

The most significant changes for manufacturers of medicinal products were:

  • The requirement to prepare annual Product Quality Reviews
  • The requirement to use quality risk management
  • Detailed procedures on stability testing
  • Detailed procedures on reference and retention samples, and
  • Several changes for the manufacture of sterile medicinal products are also included in Annex 1.

Where relevant, annexes also apply to the manufacture of APIs.

4. What are the implications of the 2009 Code on products being imported into Australia?

There are no impacts on imports, cleared by GMP certificates and other evidence of GMP compliance as outlined in the Guidance on Clearance of Overseas Manufacturers. From 1 July 2010, the TGA has conducted its overseas inspections according to the 2009 Code. This includes inspections of US manufacturers of herbal & vitamin preparations that are not inspected by the US FDA according to medicinal GMP requirements.

5. PIC/S GMP Annexes 4 and 5 are not adopted in Australia. If a domestic veterinary manufacturer is inspected by the TGA under the EU MRA, what role will Annexes 4 and 5 play?

If the TGA inspects and grants an 'MRA certificate' to a veterinary product manufacturer to enable their product to be exported to Europe, the TGA will use the relevant parts and Annexes of the 2009 Code, as well as Annexes 4 and 5.

6. Will the Australian Pesticides and Veterinary Medicines Authority (APVMA) accept TGA inspections as applicable for veterinary manufacture where a company manufactures both medicines and veterinary products?

Yes, the APVMA will accept TGA inspections of veterinary manufacture. However, requests for inspections of veterinary medicinal products in addition to human medicinal products must be conveyed to the TGA inspector prior to the commencement of the scheduled inspection.

7. What sunscreens are required to be manufactured in compliance with the 2009 Code?

Sunscreens with an SPF claim of 4 or over are required to be manufactured in compliance with GMP.

Note that cosmetic preparations which contain a sunscreen for a secondary purpose are under certain circumstances excluded from medicines regulation and regulated as cosmetics. More details are given in the Australian Regulatory Guidelines for Sunscreens (ARGS).

8. Can the Technical Guidance documents that are available for Listed Complementary medicines manufacturers also be applied for sunscreen manufacturers?

Yes, the Technical Guidance documents for Listed Complementary medicines are baseline documents, elements of which can also be applied to other medicines if justified.

9. What are the implications of the 2009 Code for medicinal gases manufacturers?

The implications for medicinal gases manufacturers are similar to those for other medicines manufacturers. The Guide for interpreting the 2002 Code for manufacturing medicinal gases has been revised to reflect the 2009 Code.

10. Has there been an assessment of the financial impact of the introduction of the 2009 Code?

The TGA prepared a preliminary assessment which was reviewed by the Office of Best Practice Regulation. The preliminary assessment recognised the impacts would vary for different classes of manufacturers, and that for many Australian manufacturers exporting abroad or who were part of a multinational group of companies, there would be no impact at all. Overall, the TGA assessed the financial impact as low.

Quality management (Chapter 1)

11. What is meant by 'marketing authorisation'?

Marketing Authorisation is a set of regulatory requirements specified on the ARTG and any other requirements imposed by a relevant Delegate of the Secretary upon product listing or registration.

Examples of regulatory requirements include, but are not limited to, compliance with registered formulations, special storage and transportation conditions, shelf life, labelling, batch release testing requirements etc.

The Marketing Authorisation is equivalent to a Certificate of Registration or a Certificate of Listing for a medicinal product under the Therapeutic Goods Act 1989.

12. Is the holder of the Marketing Authorisation the product sponsor?


13. Can a sponsor perform release for supply?

Release for supply is defined as a manufacturing step for which a TGA licence is required. For this reason, a sponsor can only perform release for supply if the sponsor holds a TGA manufacturing licence. Refer to clause 1.1vii. of the 2009 Code.

14. Can a manufacturer have more than one authorised person to perform release for supply?

Yes - a manufacturer is allowed to have more than one authorised person to perform release for supply.

If a sponsor has multiple manufacturers for a product, who should be responsible for release for supply?

The Authorised Person of the manufacturer responsible for release for supply should have a full overview of all manufacturing steps, including the ones performed by other manufacturers. Consequently, in most cases it would make sense to make the last manufacturer in the supply chain for each batch of product responsible for release for supply. However, for example where the last manufacturer in the supply chain only performs secondary packaging it would probably be better to have the responsibility for release for supply with the manufacturer performing the more crucial steps in manufacture. It could be any of the manufacturers, as long as the manufacturer's Authorised Person has full overview of all steps performed in the manufacture of the batch involved and has full access to all details of the marketing Authorisation.

16. What is the TGA's expectation during inspection in relation to marketing authorisation (regulatory compliance) of products?

The TGA expects that an authorised person must carry out release for supply to ensure the products meet all regulatory requirements. Release for supply must include assurance of compliance with the marketing authorisation, as well as meeting GMP requirements, such as assessing Product Quality Reviews and the effectiveness of the on-going stability program. This applies to both local and overseas manufacturers.

17. Does the inspection of a manufacturer's compliance with marketing authorisation refer only to products manufactured at the site of inspection, products manufactured by a third party, imported products, or all products?

Where the manufacturer being inspected is responsible for the release for supply of the product, the inspection scope includes products manufactured by that manufacturer, irrespective of whether the products are manufactured in-house (where the manufacturer is the sponsor) or whether the products are manufactured under contract. This applies to both Australian and overseas manufacturers.

Where another regulatory authority certifies an overseas manufacturer as being compliant with the PIC/S or EU GMP requirements, it will be presumed that the manufacturer meets all requirements and ensures that the marketing authorisations have complied with GMP requirements for all manufactured products.

18. Do distribution records require batch numbers?

According to Clauses 1.3(vii) and 8.13 the recording of batch numbers in distribution records is mandatory.

19. What is meant by 'all licensed products' in the first sentence of Clause 1.4, stating that Product Quality reviews (PQRs) should be conducted for all licensed products?

This refers to the manufacturing licence or, in case of overseas manufacturers, the applicable GMP clearances. This implies that domestic manufacturers are expected to conduct PQRs for all medicinal products manufactured under the manufacturing licence and overseas manufacturers are expected to conduct PQRs for all medicinal products for which a clearance is granted. Where no marketing authorisation is available, clauses and 1.4.x do not apply.

20. Do Product Quality Reviews (PQRs) have to be conducted yearly?

Yes. However, if very few batches of one product are manufactured in one year, it may also be acceptable to conduct a two yearly PQR providing a rationale is documented and scientifically justified. The justification for a reduction in the frequency of reviews should consider whether the medicines are registered, listed or complementary, the number and size of batches manufactured, whether grouping is utilised (see question 19) and the method of manufacture, together with an assessment of the risk associated with the product. The approach taken by the manufacturer will be assessed on a case-by-case basis.

21. Can one Product Quality Review (PQR) be prepared for a group of products?

Grouping (sometimes referred to as bracketing or matrixing) of products for the preparation of PQRs may be acceptable, if adequately justified. It is usually only acceptable if the amount of batches manufactured annually for each product within the group is low, the grouped products are of the same pharmaceutical form containing the same or very similar active ingredients and are manufactured using the same equipment. Acceptability will be assessed during inspections on a case-by-case basis.

22. Do all batches for which manufacture has commenced have to be included in Product Quality Reviews (PQR)s?

Yes. For example, also all batches for which the manufacture was terminated, delayed or has failed are expected to be included in the PQRs. When grouping is applied, all batches of all products in each group are expected to be included in the PQR.

23. If a company has multiple contract manufacturers, how are they supposed to perform a Product Quality Review (PQR)? Are sponsors required to obtain any evidence from overseas manufacturers?

The preparation of PQRs is a shared responsibility between the sponsor and the manufacturer(s) of a product. PQRs are expected to be available for review during inspections of manufacturers of products for which the manufacturer is responsible for release for supply. Sponsors are also expected to have access to the PQRs, to ensure product compliance with the marketing authorisation.

24. When the 2009 Code became mandatory from 1 July 2010, did the TGA expect to see PQRs readily available during inspection?

The TGA expects PQRs to be prepared as of 2011.

25. Are the TGA's expectations for PQRs for listed complementary medicines similar to those for other medicines?

Yes. A separate guidance document on this issue is available on the Technical working groups page.

26. What are the requirements for Product Quality Review (PQR) for products that are for export only?

The PQR requirements for products that are for export only are the same as the PQR requirements for all other products.

27. Why is it that Quality Risk Management is mandatory whereas Annex 20 is voluntary?

Clauses 1.5 and 1.6 of the 2009 Code make it a mandatory requirement for manufacturers to have an operational Quality Risk Management system in place to ensure that the evaluation of a risk to product quality is based on a sound, scientific basis and that risk assessments are appropriately documented. Annex 20 provides guidance only on Quality Risk Management tools that may be applied by a manufacturer when assessing the risk to product quality.

28. What is the difference between a regulated change and a change that can be made through risk assessment?

The Australian Regulatory Guidelines for Prescription Medicines (ARGPM), OTC Medicines (ARGOM) and Complementary Medicines (ARGCM) each include requirements for changes to medicines in the ARTG. These requirements are mandatory and cannot be overridden by the 2009 Code. The requirements within the 2009 Code in relation to change control and risk assessment apply to both regulated and other changes.

Personnel (Chapter 2)

29. What does 'necessary qualifications' mean in clause 2.1?

'Necessary qualifications' mean having the education, training, experience and skills or any combination of these elements that will ensure that staff can perform assigned duties and functions at an acceptable level.

30. What are the training requirements for personnel (clauses 2.8-2.12)?

Training and assessment should be carried out by persons with relevant training, qualifications and experience in the subject matter and training personnel should preferably have been formally qualified in training and assessment.

Training should be given to all people affected by significant change in the Quality Management System, e.g. when SOPs or methods of manufacture change. The requirement for initial and ongoing training should be reflected in procedures, and training records should be generated and kept.

There are a number of people who have a direct bearing on quality outcomes. These include contractors, consultants and casual employees. Therefore, appropriate training and assessment should be provided and recorded.

31. What are language requirements for personnel?

Manufacturers should define language requirements or standards and ensure personnel are proficient in the required language for their allocated tasks, particularly in relation to documenting and recording. Procedures employed to overcome identifiable deficiencies should also be documented.

Premises and equipment (Chapter 3)

32. What environment (including air supply) is required for sampling of non-sterile starting materials?

Clause 3.9 describes the physical requirements for the area being used to sample non-sterile starting materials. This sampling 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 may be used provided there are adequate controls in place to ensure that materials are contained. Consideration should be given to the use of appropriate extraction/de-dusting facilities, the qualification of the hood, the possibility of contaminating the sampled material and adjacent storage area and whether materials sampled are hazardous.

33. What environment is required for sampling primary packaging materials for non-sterile products? Can they be sampled in the warehouse?

Clause 3.9 also describes the physical requirements for the area being used to sample primary packaging material for non-sterile products. As product contact components, primary packaging materials should be sampled within an environment that adequately protects the packaging from contamination. The standard of air quality is optional and HVAC is not expected. However, sampling of primary packaging materials in an open warehouse would not be allowed.

34. What is the definition of 'campaign' manufacture?

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.

35. The Code does not reference a specific standard for air quality for non-sterile manufacturing areas. What is the relevant Australian or ISO standard to be applied?

There are no standards specific to non-sterile medicine manufacture. Manufacturers are required to demonstrate that the manufacturing environment for non-sterile products affords appropriate protection to the products, and prevents contamination. Through qualification, validation and monitoring processes manufacturers should justify that the air quality is sufficient for their non-sterile manufacturing areas. Manufacturers may wish to consult the World Health Organisation's 'Good manufacturing practice: main principles for pharmaceutical products - Heating, ventilation and air conditioning systems for non-sterile pharmaceutical dosage forms' which provides additional guidance in relation to recommended levels of air filtration.

36. What does 'certain' (as per certain additional products, certain antibiotics, certain hormones etc) in clause 3.6 of the Code mean?

'Certain' refers to materials known to cause specific (side) effects in low doses. For example, 'certain antibiotics' refers to antibiotics, usually of the beta lactam group, which are known to cause allergic reactions. 'Certain hormones' refers to hormones that can have pharmacological effects if trace amounts cross-contaminate other products. Examples are estrogens and some progesterone-like hormones. Manufacturers should evaluate materials that are processed and ensure that adequate control measures are in place.

37. The Code appears to contain very little detail on requirements for cleaning and sanitisation. What will the TGA consider an acceptable standard for these requirements?

The Code is not prescriptive on cleaning and sanitisation, as it considers the manufacturer to be responsible for demonstrating that the applied cleaning and sanitisation procedures are suitable for its intended purpose. This can be demonstrated by qualification, validation or monitoring studies. The level of depth of these studies may depend on the nature and types of products manufactured.

38. Is a facility that is used as a warehouse and distribution centre AFTER release of a pharmaceutical product, required to comply with the Code of 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, warehousing and distribution after release for supply and after the product has left the manufacturer's control, is not currently regulated by the TGA. Hence, a licence is not required if a facility is used only for warehousing and distribution. However, there may be State regulatory requirements that are applicable which should be checked with the relevant State Department.

Production (Chapter 5)

39. What are the TGA's expectations on validation for listed complementary medicines manufacture?

A separate guidance document is available for this: Technical guidance on the interpretation of manufacturing standards: Process validation for Listed complementary medicines

40. What are the TGA's expectations on supplier qualification for listed complementary medicines manufacture?

A separate guidance document is available for this: Technical guidance on the interpretation of manufacturing standards: Supplier qualification

41. What are the requirements regarding unique batch numbering? Is a batch number required to only designate one batch of a product from other batches of that product, or is a unique batch number required for each product-and-batch combination?

The issue of batch numbering is dealt with in Therapeutic Goods Order No. 69 General Requirements for Labels for Medicines. 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 for batch numbering meets these requirements and is effective.

Unpacked bulk products, should have a batch number that is unique to both product and batch, to minimise the potential for mix-ups during manufacturing. For finished products which are easily distinguished, a batch numbering system that only designates batches from that product may be acceptable.

42. 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-ups.

Quality control (Chapter 6)

43. What are the TGA's expectations on sampling and testing for listed complementary medicines?

A separate guidance document is available for this: Technical guidance on the interpretation of manufacturing standards: Sampling and testing of complementary medicines

44. Is it necessary to conduct on-going stability studies at a GMP certified laboratory?

No. However, the results from these studies are required to be reliable and meaningful. For that reason, other certificates may be used in lieu of a GMP certification, such as a current Good Laboratory Practice (GLP) certificate or licence issued by a regulatory authority acceptable to the TGA or a current ISO 17025 accreditation certificate. Stability test methods used by the laboratory should be appropriately validated and documented according to the requirements of the Code.

The results from the on-going stability monitoring studies must be considered as part of release for supply, which is the final step in manufacturing.

45. In the case of imported medicines, is the responsibility to conduct an on-going stability monitoring program with the manufacturer or with the sponsor?

The responsibility is with both the manufacturer and the sponsor. The manufacturer who carries out release for supply needs to ensure that the batch meets its Marketing Authorisation, and that an on-going stability monitoring program is conducted and data is available to support the expiry date. The sponsor is responsible for the Marketing Authorisation, ensures an on-going stability testing program is performed and has access to the stability results. In the contract manufacturing agreement, the responsibility for on-going stability may be contracted out to the manufacturer or other parties.

46. Where bulk medicines are imported into Australia to be packaged by a domestic manufacturer, may the on-going stability program of the bulk manufacturer be used?

No. On-going stability is required to be performed in the packaging material in which the product is marketed in Australia. The overseas bulk manufacturer will use different packaging equipment and processes although the packaging materials might be the same.

47. Are the TGA's expectations for on-going stability studies for listed complementary medicines similar to those for other medicines?

Yes. A separate guidance document on this issue is available on the Technical working groups page.

48. Is grouping of products in the on-going stability program acceptable?

Grouping or bracketing could be acceptable, if appropriately scientifically justified and if the formulation is (nearly) identical. This will be assessed during inspections on a case-by-case basis.

49. Are on-going stability data reviewed during inspections?

Yes. During inspections, the operation of an appropriate on-going stability program are reviewed, including the results of on-going stability studies, where appropriate. If there are any concerns, the inspector can refer the evaluation to the regulator.

50. In which cases are the outcomes of the on-going stability program to be communicated to the regulator?

Although it is acknowledged that some normal variability in the results of on-going stability studies can be expected, all statistically significant departures from established stability profiles must be notified to the regulator.

51. Should the results of the on-going stability program be part of the release for supply process?

Yes, the results of the on-going stability program are expected to be available to the Authorised Person who should consider those before releasing a batch for supply.

Complaints and product recall (Chapter 8)

52. What requirements are included in the 2009 Code regarding counterfeit products?

Clauses 8.7 and 8.8 require that the procedures on complaints handling should include an assessment for counterfeit products. If counterfeiting is detected the TGA must be notified.

Manufacture of sterile medicinal products (Annex 1)

53. What are the main changes in Annex 1 and how does the TGA interpret these changes?

The PIC/S has prepared and published a recommendation document for interpretative guidance on the revised Annex 1, which is called Technical interpretation of revised Annex 1 to PIC/S GMP Guide, PI 032-2. This document gives both a detailed overview of the most significant changes in Annex 1, as well as a technical interpretation. The document is endorsed by the TGA: Revised technical interpretation of Annex 1 to PIC/S GMP guide.

54. Are negative pressure containment isolators which are used for closed system preparations, considered separate in relation to the preparation of beta lactam antibiotics like penicillins (ref. to Clause 3.6 of the general part)?

Generally, 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.

55. Where in GMP does clean room apparel fit in? Can manufacturers of such apparel be licensed as a manufacturer of starting material?

Clean room apparel is not a therapeutic good and manufacturers of such apparel are not subject to inspection and licensing under the Therapeutic Goods Act 1989. However, licensed manufacturers of sterile medicinal products should qualify their vendors of critical goods used in the clean rooms, such as clean room apparel.

Manufacture of biological medicinal products (Annex 2)
56. 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
57. Is Annex 2 applicable to the manufacture of APIs used in biological medicinal products?

Yes. The manufacture of APIs for biological medicinal products for human use is usually performed in immediate conjunction with the manufacture of the biological medicinal product itself. For that reason, Annex 2 is written to cover both the API and the finished product manufacuring steps of biologicals. Additionally, Part II of the Code is applicable to the manufacture of APIs for biological medicinal products.

Manufacture of radiopharmaceuticals (Annex 3)

58. What are the implications of the new Code for manufacturers of radiopharmaceuticals?

The implications for radiopharmaceuticals manufacturers are similar to those for other medicines manufacturers. The Guide to interpretation of the 2002 Code for manufacturing the PET radiopharmaceutical Fludeoxyglucose [18F] Injection has been revised to reflect the 2009 Code.

59. Are hospitals supplying radiopharmaceuticals to other hospitals required to obtain a TGA licence?

Yes, with one exemption, which is for public hospitals supplying radiopharmaceuticals to other hospitals or public institutions in the same State or Territory. In that case the biomedical engineers, radiochemists and pharmacists employed by those public hospitals are exempted from the requirement to obtain a TGA licence to manufacture radiopharmaceuticals.

60. Are radiopharmaceuticals supplied in a hospital situation required to be entered in the ARTG?

Yes, except for radiopharmaceutical cold kits to which a radioisotope is to be added immediately before injection into patients. Registration is not required if the cold kit is manufactured in a public or private hospital for a patient of that hospital or a patient of another public or private hospital in the same State or Territory.

Manufacture of herbal medicinal products (Annex 7)

61. If actives or 'marker compounds' in herbal products are identified but no primary standards are commercially available, how can assays be conducted?

If a marker compound is selected, a suitable reference material of that compound should be obtained from external or internal sources.

62. Does the TGA interpret 'quantified at input' to be equivalent to 'Standardized to contain' in the context of active claims on herbal medicines?

The TGA position on this issue has not changed. Please refer to the Guidance for the use of the term 'quantified by input' for complementary medicines manufacturers.

Sampling of starting and packaging materials (Annex 8)

63. 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 inspection. Such validation should comprise a number of actions, which may include all or most of the following:
    1. The use of a questionnaire prepared by the potential customer and completed by the potential supplier, concerning the supplier's operating Quality System.
    2. Approval inspection 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 inspection reports of other regulatory authorities by the potential customer is normally not sufficient, unless it can be demonstrated that the inspection covered the specific operations to be used in the processing of materials for the potential customer.
    3. 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 inspector. Sampling by the suppliers should be validated.
    4. A program for regular re-inspection 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.
    5. 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 e.g. a Certificate of Suitability of Monographs of the European Pharmacopoeia, does not replace an inspection.
64. In what cases could √n+1 sampling be applied?

Where a validated procedure is established to justify reduced sampling, and scientific and statistical evidence is presented, √n+1 sampling may be justified as applicable.

Manufacture of investigational medicinal products (Annex 13)

65. 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 inspection 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 inspection (including Annex 13) and licensing by the TGA.

66. Would a dedicated pilot facility for the development of dosage forms and new products, which is not used for the manufacture of saleable product, be subject to TGA inspecting and licensing?

If the dedicated pilot facility is used to manufacture investigational medicinal products for clinical trials in Phase 2 or later (or for commercial supply) the facility is subject to inspecting and a TGA licence or clearance is required.

67. What is meant by 'certain characteristics' in clause 32 of Annex 13?

The 'certain characteristics' in clause 32 refers to non-commercial clinical trials performed by researchers without the participation of the pharmaceutical industry. These trials are usually performed with registered (or listed) products that are obtained from the market for use in a clinical trial. The requirements in this clause relate to the way these products are to be labelled.

Qualification and validation (Annex 15)

68. How do PIC/S recommendation documents like PI-006-3 Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation and PI-007-5 Recommendations on the Validation of Aseptic Processes relate to the Code?

These documents are for guidance only. The TGA encourages the use of these Recommendation documents as they expand on clauses 5.21, 5.22, 5.23, 5.24 and Annexes 1 and 15 of the Code.

69. Is it necessary to revalidate an already established and previously validated process?

Validation is required to ensure that therapeutic goods consistently meet 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 would not justify exemption from validation (e.g. 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.

70. 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. Process validation is not required for intermediate batch sizes if it could be demonstrated, based on risk assessment, that process consistency can be achieved for any intermediate batch size.

71. Should the scope and extent of validation be based on risk?

Yes, the scope and extent of validation should be based on risk according to the manufacturer's quality risk management procedures. Qualification and validation work is required to control the critical aspects of the particular operation and a common sense approach should be applied.

72. Is performance qualification (PQ) required to be carried out for each item of critical process equipment, if process validation is performed on the same equipment?

PQ is required to be preceded by IQ and OQ.

For significant changes to equipment (eg. for new or modified items of equipment), the PQ is separate from and precedes process validation. For minor changes not impacting on already qualified equipment (eg. to processing parameters only), process validation could be integrated in PQ and a repeated IQ and OQ may not be necessary.

73. What are the TGA's expectations for process validation for complementary medicines manufacture?

A separate guidance document for this is available: Technical guidance on the interpretation of manufacturing standards: Process validation for Listed complementary medicines

Reference and retention samples (Annex 19)

74. What is the difference between a reference sample and a retention sample?

A reference sample is a sample for the purpose of future analysis, which could refer to starting materials, packaging materials or finished products.

A retention sample is a sample representing the batch of finished product as distributed.

75. Can items from the stability program be used as retention samples?


76. For multipack products, do the complete multipacks need to be retained as samples?

Not necessarily. The requirement is that the amount of retention samples is sufficient to carry out analytical work during the entire shelf life of the product.