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PE009-13, the PIC/S guide to GMP for medicinal products

TGA interpretation and expectations for demonstrating compliance

2 January 2018

Book pagination

Quality management (Chapter 1)

Terminology for quality management

Pharmaceutical Quality System

In the latest PIC/S Guide to GMP, the terminology 'Quality Management System' has been replaced with the term 'Pharmaceutical Quality System' (PQS). This is in line with ICH Q10 global harmonisation efforts, PIC/S Harmonisation efforts and to align the GMP guide with contemporary principles of quality systems management. The new terminology better reflects the specific design elements and requirements for a quality system used to manage the manufacture of medicinal products. The Pharmaceutical Quality System approach described within PIC/S Guide to GMP (PE009-13) is applicable to the manufacture of all therapeutic goods to which the PE009-13 applies.

Manufacturing authorisation

The term 'manufacturing authorisation', generally refers to the Licence to Manufacture Therapeutic Goods issued by the TGA to domestic manufacturers. For manufacturers located overseas, this would refer to the Certificate of GMP Compliance issued following an inspection.

Marketing authorisation

A marketing authorisation, (MA) is the approval given to supply a therapeutic good in Australia, and, in most cases, involves entry on the Australian Register of Therapeutic Goods (ARTG).

The marketing authorisation includes the details of the product in the Australian Register of Therapeutic Goods (ARTG), as well as all other matters in relation to product registration, listing or inclusion agreed in writing between the TGA and the sponsor, and any other requirements imposed by a relevant Delegate of the Secretary upon ARTG entry.

Examples of regulatory requirements include, but are not limited to:

  • compliance with standards and registered formulations
  • special storage and transportation conditions
  • shelf life
  • packaging and labelling
  • batch release testing requirements

Manufacturers are responsible for ensuring their Pharmaceutical Quality Systems are designed and operated to ensure all relevant requirements of the marketing authorisation are observed during the manufacture of medicines.

Holder of the marketing authorisation

The holder of the marketing authorisation is the product sponsor.

Change management

Regulated changes

Manufacturing changes that affect the product registered details are regulated and are included as requirements for the marketing authorisation of therapeutic goods:

  • prescription medicines (ARGPM)
  • OTC medicines (ARGOM)
  • complementary medicines (ARGCM)
  • biologicals (ARGB)

These requirements are mandatory and are in addition to the requirements of the PIC/S Guide to GMP (PE009-13). The requirements within the PIC/S Guide to GMP (PE009-13) in relation to change control and risk assessment apply to both regulated and other changes.

Change control applies to all GMP-related activities

Change control is included in Chapter 1 (Clause 1.4 xii, xiii), PE009-13. This clarifies the existing expectation that change control does not just apply to validation activities, but to all GMP-related activities undertaken by a manufacturer.

Any changes to existing processes, systems, facilities, equipment, products, documents, etc. should be evaluated through a change control process. The effort and extent of change control processes should be commensurate with the nature of the change and based on risk management principles.

All changes implemented should be verified for their effectiveness following implementation.

Managing deviations

There are no changes to the expectations for managing deviations and other similar events (Clause 1.4 xiv). However, PE009-13 now provides clarity regarding the expectations for the investigation of deviations, including adequate root-cause-analysis and identification of corrective and preventative actions.

Release for supply

For more information on release for supply (RFS), refer to:

Release for supply is defined as a manufacturing step for which a TGA licence is required. For this reason, a sponsor can only perform batch certification for the purposes of release for supply (clause 1.4xv) if:

  • the sponsor holds a TGA manufacturing licence


  • the licensed sponsor is authorised within the marketing authorisation for that step in manufacture

Having more than one authorised person for RFS

A manufacturer is allowed to have more than one Authorised Person to perform release for supply. It is the manufacturer's responsibility to ensure that each Authorised Person is appropriately trained and experienced and that the job function relating to release is clearly documented and explained in the Pharmaceutical Quality System.

Authorised Person needs full overview of all manufacturing steps

The Authorised Person responsible for release for supply should have a full overview of all manufacturing steps, including the ones performed by other manufacturers. Consequently, the last manufacturer in the supply chain for each batch of product is normally responsible for release for supply. However, the Authorised Person may be identified from any of the manufacturers authorised for release for supply in the marketing authorisation, as long as they have full overview of all steps performed in the manufacture of the batch involved and have full access to all details of the marketing authorisation.

RFS includes consideration of marketing authorisation requirements

The TGA expects an Authorised Person to 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 all relevant GMP requirements, including assessing Product Quality Reviews and the effectiveness of the on-going stability program. This applies to inspections of both Australian and overseas manufacturers.

Senior management responsibilities for GMP and quality management

New clauses in PE009-13 (including clause 1.5) place particular emphasis on the roles and responsibilities of senior management who have ultimate control over manufacturing facilities and activities. Senior management hold the responsibility to make sure that adequate resources are available (human, financial and physical) in order to ensure that the manufacturing activity is managed appropriately.

It is expected that senior management ensure that an effective PQS is implemented and undertake an active role in the support, development and implementation of the PQS. Under the new PE009-13, senior management are ultimately responsible and accountable for the effectiveness of the PQS.

Management reviews

Management reviews (clause 1.6) are a basic quality system element designed to collate, evaluate and communicate details of the effectiveness of the PQS to the management group. Management reviews are particularly important in escalating concerns and enabling senior management support with the aim of resolving issues and managing risks. The TGA's basic expectations, based on ICH Q10 principles are that the management review system should include:

  • The results of regulatory inspections and findings, audits and other assessments, and commitments made to regulatory authorities
  • Periodic quality reviews, that can include:
    • measures of customer satisfaction such as product quality complaints and recalls
    • conclusions of process performance and product quality monitoring
    • the effectiveness of process and product changes including those arising from corrective action and preventive actions
  • Any follow-up actions from previous management reviews

The management review system should identify appropriate actions, such as:

  • improvements to manufacturing processes and products
  • provision, training and/or realignment of resources
  • capture and dissemination of knowledge

Management Review of the Pharmaceutical Quality System. Management should have a formal process for reviewing the PQS on a periodic basis. The review should include:

  1. Measurement of achievement of PQS objectives;
  2. Assessment of performance indicators that can be used to monitor the effectiveness of processes within the pharmaceutical quality system, such as:
    1. complaint, deviation, corrective and preventative actions (CAPA) and change management processes
    2. feedback on outsourced activities
    3. self-assessment processes including risk assessments, trending, and audits
    4. external assessments such as regulatory inspections and findings and customer audits

Monitoring of internal and external factors impacting the PQS monitored by management can include:

  1. emerging regulations, guidance and quality issues that can impact the PQS
  2. innovations that might enhance the PQS
  3. changes in business environment and objectives
  4. changes in product ownership
Frequency of management reviews

TGA inspectors would generally expect reviews to be conducted at least annually (clause 1.6). However, management reviews may be performed more frequently for new operations, sites that have not previously performed management reviews and sites where the initial management review identifies a number of issues that require rectification.

Also, more frequent reviews may be required for sites with larger and more diverse manufacturing operations.

Development of a quality manual

Clause 1.7 in PE009-13 requires a Quality Manual (or equivalent document) to be written and maintained. A quality manual or equivalent should be established and should contain the description of the pharmaceutical quality system. The description should include:

  • the quality policy
  • the scope of the PQS
  • identification of the PQS processes, as well as their sequences, linkages and interdependencies. Process maps and flow charts can be useful tools to facilitate depicting PQS processes in a visual manner
  • management responsibilities within the PQS

Product distribution expectations

Clause 1.8 (ix) states that the distribution of the products minimises any risk to their quality and takes account of 'good distribution practice'.

The TGA does not currently inspect the wholesale distribution of therapeutic goods that have been released for supply.

  • The responsibility for oversight of wholesale of medicines in schedules 2, 3, 4 & 8 of the Poisons Standard currently sits with the states and territories, who may issue relevant permits and licences for wholesalers.
  • For medicines that are not in schedules 2, 3, 4 & 8 of the Poisons Standard and relevant biologicals, sponsors and manufacturers hold shared responsibility for ensuring that they are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life. These responsibilities should be clearly identified within Quality or Technical Agreements between the manufacturing site and Australian Sponsor.

TGA inspections do include an evaluation of the transport conditions for starting materials, bulk and packed medicines between sites of manufacture and clause 1.8 (ix) would apply in these circumstances.

Good distribution practices in the case of Australia would be limited to the application of transport requirements specified in Annex 15 of the PIC/S GMP guide and not necessarily any other official GDP guideline.

Product Quality Reviews (PQRs)

Guidance regarding the documentation requirements for PQRs may be found in the TGA Guidance for Release for Supply.

PQR for Authorised products

'All authorised products' in clause 1.10 refers to all products manufactured, within the reviewed time period, under a manufacturing authorisation. 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 GMP clearance is granted.

PQRs for listed medicines

Manufacturers of listed medicines are expected to generate PQRs in accordance with GMP requirements. In conjunction with industry, we have developed specific guidance for the generation of PQRs for listed complementary medicines.

For more information see our guidance about PQRs for listed complementary medicine manufacturers. This guidance will be revised to reflect the PIC/S Guide to GMP (PE009-13) as required and in consultation with industry.

PQRs for export-only medicines

The PQR requirements for products that are for export only are the same as the PQR requirements for all other products, refer 'Export-only medicines' section above.

PQRs for products with no marketing authorisation (e.g. compounded medicines)

Product Quality Reviews are performed to demonstrate the consistency of the manufacturing process. Where no marketing authorisation is available, clauses and 1.10.x do not apply, but a review of the process consistency, including all other elements of clause 1.10 should be performed and documented by the manufacturer.

Supply chain traceability for active substances

Manufacturers of dosage forms should have a clear understanding of the approved suppliers of active substances, and each entity and their responsibility in the supply chain between the site of manufacture and receipt (clause 1.10(i)). Supply chains should be adequately secure, integral and ensure that materials are transported under appropriate conditions. Supply chains should be mapped and any identified risks managed following the principles of quality risk management.

Guidance for the evaluation of supply chains for active materials used in non-sterile and complementary medicines may be found in our guidance about Supplier Qualification. This guidance will be revised to reflect the PIC/S Guide to GMP (PE009-13) as required and in consultation with industry.

Frequency of PQRs

It is important that manufacturers perform a review of all relevant elements of clause 1.10 on at least a yearly basis; however, where very few batches of one product are manufactured in one year, or no manufacturing takes place, it may also be acceptable to perform a full PQR on a two yearly basis providing a rationale is documented and scientifically justified.

For periods where very few batches of one product are manufactured in one year, or no manufacturing takes place, it is expected that manufacturers and sponsors maintain vigilance over elements of clause 1.10 that do not directly relate to manufacturing activities, e.g. results of ongoing stability, returns, recalls and complaints that may provide information regarding products available in the market.

Grouping of products for PQR

Grouping (sometimes referred to as bracketing or matrixing) of products is when one PQR is prepared for a group of products. Grouping 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 of grouping will be assessed during inspections on a case-by-case basis, and with consideration to any applicable GMP guidance.

Batches to be included in a PQR

All batches for which manufacture has commenced are expected to be included in a PQR. In addition, all batches for which the manufacture was terminated, delayed or has failed are also 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.

Shared responsibility for PQRs between manufacturers and the sponsor

Preparation of PQRs is a shared responsibility between the sponsor and the manufacturer(s) of a product. Manufacturers and sponsors should design and implement effective systems to ensure that PQR reports and relevant data are supplied, compiled and reviewed. Responsibilities in relation to PQRs should be clearly defined within technical agreements between parties.

Each manufacturer in the supply chain is expected to generate and hold PQRs relevant to the specific manufacturing step they are undertaking. These are expected to be supplied to the sponsor and available for review during inspections of manufacturers.

The full PQR containing all relevant sections from all manufacturers should be held and reviewed by Authorised Persons performing the release for supply step. Sponsors are also expected to have access to the PQRs, to ensure product compliance with the marketing authorisation.

Quality risk management

Quality risk management is mandatory

Clauses 1.12 and 1.13 of Part I (also and clauses 2.20 and 2.21 of Part II) of PE009-13 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 is voluntary and provides guidance only on Quality Risk Management tools that may be applied by a manufacturer when assessing the risk to product quality.

Book pagination