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Guidance on licensing/certification inspections
Version 1.0, April 2013
The inspection process
Inspections can be performed by single inspectors or inspection teams. In the case of a team inspection, the team will be led by a Lead Inspector bearing overall responsibility for the Inspection.
The Lead Inspector can be supported by appropriately qualified and experienced inspectors and, where required, technical specialists acting as advisors to the inspectors. Technical specialists bring to the Inspection Team current specialised knowledge of the activities being inspected and ensure that the inspection provides a relevant and practical review of aspects critical to the manufacture of therapeutic goods.
The inspection process is based on a 'paperless' approach, meaning that all communications relating to the inspection (announcement, report, close-out record and close-out letter) are issued as electronic documents only. Manufacturers are requested to submit any documents of which the inspector asks to take a copy, as e-documents only.
The TGA uses the following definitions in relation to Inspection related terminology:
Systematic, independent and documented process for obtaining inspection evidence and evaluating it objectively to determine the extent to which the inspection criteria are fulfilled (ISO19011 - Clause 3.1)
Note: When two or more inspecting organisations cooperate to inspect a single manufacturer, this is termed a joint inspection.
Set of policies, procedures or requirements (ISO19011 - Clause 3.2)
Note: Inspection criteria are used as a reference against which inspection evidence is compared.
Records, statements of fact or other information, which are relevant to the inspection criteria and verifiable (ISO19011 - Clause 3.3)
Results of the evaluation of the collected inspection evidence against inspection criteria (ISO19011 - Clause 3.4)
Note: Inspection findings can indicate either conformity or nonconformity with inspection criteria or opportunities for improvement.
Outcome of an inspection, provided by the inspection team after consideration of the inspection objectives and all inspection findings (ISO19011 - Clause 3.5)
Extent and boundaries of an inspection (ISO19011 - Clause 3.13)
Note: The inspection scope generally includes a description of the physical locations, organisational units, activities and processes, as well as the time period covered.
Action to eliminate the cause of a detected deficiency or nonconformity or other undesirable situation (ISO 9000 Clause 3.6.5)
Action to eliminate a detected deficiency or nonconformity (ISO 9000 Clause 3.6.6)
Note: There is a distinction between corrective action and correction. Corrective actions are made against an identified root cause, whereas corrections are made against individual examples of a core issue. A correction can be, for example, rework or regrade.
There can be more than one root cause for any deficiency or nonconformity.
A correction can be made in conjunction with a corrective action.
Non-fulfilment of a requirement (for medicines inspections; ISO 9000 Clause 3.6.2)
Non-fulfilment of a requirement (for devices inspections; ISO 9000 Clause 3.6.2)
Data supporting the existence or verity of something (ISO 9000 Clause 3.8.1)
Note: Objective evidence may be obtained through observation, measurement, test, or other means.
Action to eliminate the cause of a potential deficiency or nonconformity or other undesirable potential situation (ISO 9000 Clause 3.6.4)
Recurring deficiency or nonconformity:
Deficiency or nonconformity that was also identified at a previous inspection, for which apparently the corrective and preventative actions taken earlier were inadequate.
Although most inspections are announced, unannounced inspections may be performed where required. Inspections are announced via telephone (to the manufacturer or the sponsor) followed by an announcement letter to the manufacturer. Like all inspection correspondence, announcement letters are signed electronically and sent via email only.
Inspection preparation involves collection and review of all necessary documents and data relating to the manufacturer and the inspection. Preparation for inspection includes the following documents:
- Any applicable applications or variations
- Departmental files on the manufacturer (electronic and hard copy), for re-inspections in particular the previous two Inspection reports and Closeout records
- Manufacturing steps (Site Authorisations) and Conditions of the licence (domestic inspections) or certificates and clearances (overseas inspections)
- Recalls that have occurred since the previous inspection
- Outcomes of any product testing performed by the TGA Office of Laboratories and Scientific Services
- Regulatory issues
- Therapeutic goods entered into the ARTG and the related Marketing Authorisations
- Site Master File
- Documents provided by the manufacturer (or sponsor)
- An Inspection plan and an Inspection attendance sheet are prepared. The Inspection plan is handed to the manufacturer only at the start of the inspection.
Conduct of an inspection
Roles and responsibilities
The inspection may be performed by a single inspector or an inspection team. In case of an inspection team, the Lead Inspector manages the team and has oversight of all phases of the inspection. Where required, the inspection team may include specialists from other TGA Offices. Specialists have the same responsibilities as inspectors.
The team may be accompanied by guides or observers. Attendance of any guides or observers on initiative of the TGA will be communicated by the Lead Inspector to the manufacturer prior to the inspection. Guides or observers should not influence or interfere with the conduct of the inspection and are subject to confidentiality.
Guides or observers to the inspection on initiative of the manufacturer could be the manufacturer's key personnel or any witnesses on behalf of the manufacturer or interpreters arranged for by the manufacturer. When guides are appointed by the manufacturer, they should not influence or interfere with the conduct of the inspection. Guides should assist the inspection team, and act on the request of the inspection team.
Their responsibilities may include the following:
- Providing clarification or assisting in collecting information
- Ensuring that rules concerning site safety and security procedures are known and respected by the inspection team members
- Witnessing the inspection on behalf of the manufacturer
- Translating for the inspection team in the case of inspections involving foreign languages.
Observers may for example be representatives of other regulatory bodies. Observers may accompany the inspection team but must not influence or interfere with the conduct of the Inspection.
On arrival at the manufacturer's premises, the Lead Inspector chairs an opening meeting with the manufacturer's management team. At this meeting:
- Members of the inspection team are introduced, including an outline of their roles
- The scope and objectives of the Inspection are confirmed
- The Inspection plan is discussed and confirmed
- A tentative time and date for the closing meeting and any interim meetings of the inspection team and the manufacturer's management are established
- The methods and procedures to be used to conduct the inspection are outlined
The manufacturer is advised they will be given sufficient opportunity to respond to potential issues identified. Opportunities typically include, but are not limited to:
- At the moment the issue is found
- At the daily debrief (if applicable)
- During the closing meeting
- After the closing meeting in appropriate cases
- Communication links between the Inspection team and manufacturer are established
- The language (English) to be used during the inspection is reconfirmed (especially for overseas Inspections)
- A record of attendance at the opening meeting is kept.
Collecting and verifying information
During the inspection, information relevant to the inspection objectives, scope and criteria, including information relating to interfaces between functions, activities and processes is reviewed by appropriate sampling and verified. The inspection evidence is based on samples of the available information. Inspections should be objective and related to the written current Code or Standard.
Unless a special inspection for a specific purpose, all areas relevant to the scope of manufacture are inspected for compliance with the relevant manufacturing standard specified in the current Manufacturing Principles. Any other regulatory requirement(s) that are relevant to GMP or QMS compliance are also included in the inspection (e.g. ARTG listing/registration, TGOs, Pharmacopoeias).
Shorter 'surveillance' inspections are only applicable to device manufacturers.
For medicine manufacturers critical elements include: validation (process, cleaning, QC test methods and computerised systems), complaints, deviations, change control, release for supply, starting material control and documentation/records.
Methods to collect information include:
- Interviews of personnel at all levels within the organisation
- Observation of activities, including reviewing and evaluating systems and procedures for compliance and effectiveness
- Review of documents, ie. a sufficient sample of records so that the number of records for each activity since the last inspection is adequately represented; reviewing logs and databases to show appropriate monitoring and trending has taken place
- Taking photocopies of documents or photographs.
It is a standard condition that licence holders allow documents to be copied and photographs to be taken (see s 40(4) of the Act). Where possible, electronic copies of documents are preferred.
Generating inspection findings
Inspection evidence is evaluated against the inspection criteria, ie relevant Code or Standard, to generate inspection findings. Inspection findings can indicate either compliance or non-compliance with the applicable standard in the Manufacturing Principle.
Full compliance with GMP/QMS requirements is expected. For example, where validation is required, this is expected for relevant processes for every product/product group and similarly it is expected that every starting material is properly tested according to GMP/QMS requirements and agreed interpretations. Every batch of every product must be made in full compliance with the applicable standard in the Manufacturing Principle.
The inspection team confers prior to the closing meeting to:
- Review the inspection findings against the relevant Code or QMS Standard
- Review the evidence and any other information collected during the inspection, against the relevant Code or QMS Standard
- Agree on the inspection conclusions
- Prepare an overview of issues identified during inspection (i.e. the potential deficiencies/nonconformities)
- Discuss Inspection follow-up, if included in the Inspection plan.
The Inspection team considers the nature and significance of the deficiencies/nonconformities identified and prepares a written overview of issues for presentation to the manufacturer during the closing meeting.
- A closing meeting will be held at the end of the Inspection to present the inspection findings and conclusions. All items discussed are recorded and a copy of this record is provided to the attendees of the closing meeting.
- The Lead Inspector will provide a verbal overview of the inspection and its outcome, and verbally detail any issues identified. Findings of special significance will be emphasised, particularly those regarded as issues that could result in action to suspend or revoke the licence or certificate.
- Any diverging opinions regarding the inspection findings and conclusions between the inspection team and the manufacturer are discussed and if possible resolved. If not resolved, all opinions will be recorded.
- In the case of a pre-licence inspection, the likely terms of the licence conditions are discussed and documented.
- A record of attendance is kept using the same record used during the opening meeting.
Following the on-site inspection, the inspection team prepares a report which includes the inspection findings and a summary of the overall compliance of the manufacturer's operations against the requirements of the relevant Codes and Standard(s). Like all inspection correspondence, the Inspection report is signed electronically and issued via email to the manufacturer.
Inspection report template
The template of the TGA's Inspection reports is standardised and based on the internationally harmonised template PI013-3 provided by the Pharmaceutical Inspection Co-operation Scheme (PIC/S), refer to <http://www.picscheme.org>. However, this harmonised template allows for minor differences in format and approach, for example as a result of requirements from legislation or international agreements. The main difference is that the TGA's Inspection report template does not include a Conclusion section, as the conclusion is only drawn after review of the manufacturer's response during the close-out process, and consequently the conclusion is reflected as a 'final compliance rating' in the close-out letter (see below).
The TGA Inspection report template also allows for some minor differences between reports for the different TGA Inspection programs (medicines, APIs, medical devices, blood and tissue products etc.).
Inspection reports consist of five distinct sections:
- Inspection related data, including:
- Details of the inspected site and activities carried out
- Inspection details, including inspection type, scope, date and inspectors names and roles
- Reference to the Manufacturing Standard used
- Introduction and summary of the inspection activities, including the purpose of the Inspection and the product range
- Description of inspection findings and observations. This section is typically subdivided into paragraphs referring to the chapters of the Manufacturing Standard used, as far as applicable to the manufacturer. This section also includes evidence sighted for closing out or downgrading previous inspection findings
- List of deficiencies/nonconformities observed. Manufacturers are required to respond to all deficiencies/nonconformities listed. The requirements and expectations for this response are outlined in the cover letter that is sent with the report
- The name and signature of the person authorising the report on behalf of the TGA.
The Inspection Report should not ordinarily vary from the verbal report presented to the manufacturer at the closing meeting and the record of items for discussion presented during the closing meeting.
Inspection reports are reviewed prior to being issued to the manufacturer. During this review, inspection findings are classified as critical/major/other (for medicines inspections) or major/minor (for devices inspections).
Classification of deficiencies/nonconformities
Deficiencies identified during medicines Inspections are classified as critical, major or other based on the internationally harmonised definitions provided by the Pharmaceutical Inspection Co-operation Scheme (PIC/S) in their document PI013-3, refer to <http://www.picscheme.org>. Nonconformities identified during devices Inspections are classified as major or minor. The definitions of these classifications are also included in the Inspection report.
A Critical Deficiency is a deficiency when it is observed that:
- A practice or process has produced, or may result in, a significant risk of producing a product that is harmful to the user; and/or
- The manufacturer has engaged in fraud, misrepresentation or falsification of products or data.
Examples of Critical Deficiencies for medicine manufacturers are provided in Appendix 2.
A critical deficiency is a serious situation that will result in regulatory action being considered. This classification is not applicable to Medical Device Inspections.
A Major Deficiency/Nonconformity is a non-critical deficiency/nonconformity that:
- Has produced or may produce a product which does not comply with its marketing authorisation (in some circumstances this could be critical); and/or
- Indicates a major deviation from the Code of GMP or QMS standard; and/or
- Indicates a major deviation from the terms of the manufacturing licence, GMP approval (overseas manufacturers), or Conformity Assessment Certificate; and/or
- Indicates a failure to carry out satisfactory procedures for release of batches; and/or
- Indicates a failure of the person responsible for QA/QC to fulfil his/her duties; and/or
- Consists of several other deficiencies/non conformities, none of which on their own may be major, but which may together represent a major deficiency and should be explained and reported as such.
Examples of Major Deficiencies for medicine manufacturers are provided in Appendix 2.
Examples of Major Nonconformities for medical device manufacturers are provided in Appendix 3.
An Other Deficiency Minor Nonconformity is a deficiency/nonconformity that cannot be classified as either critical or major, but indicates a departure from the applicable standard.
In the case where the inspection outcome is a provisional compliance rating of unacceptable, the inspection is referred to a Review Panel. The Review Panel is convened and chaired by a TGA manager who has not been involved in the inspection and consists of other inspectors (who also have not been involved in the inspection) and, where applicable, representatives of the Office(s) involved in the ARTG entry and/or the Office of Laboratories and Scientific Services. The Review Panel reviews the inspection, undertakes a risk assessment of the manufacturer and prepares recommendations to the Delegate for regulatory actions as applicable.
The manufacturer is required to respond to the deficiencies/nonconformities identified in the Inspection report. The process of manufacturer response and Inspector review of the response is called close-out.
Purpose and scope of close-out
The purpose of the close-out process is to ensure the manufacturer commits to perform appropriate corrective and preventative actions for each deficiency/nonconformity within an acceptable period. The close-out correspondence will record this commitment as well as the inspection team's comments and agreement. The close-out letter provides final approval of the close-out, including the close-out correspondence.
The scope of the close-out is limited to those deficiencies/nonconformities that are listed in the Inspection report. Manufacturers are not required to respond to any statements in the body of the report, but may comment on it if they consider a statement not reflecting the actual situation.
Corrections and corrective actions
One should be mindful of the definitions of a corrective action as opposed to a correction. A corrective action is an action intended to eliminate the root cause of the deficiency/nonconformity, and thus to prevent recurrence. A correction is an action to eliminate a deficiency/nonconformity, or the individual examples of a grouped deficiency/nonconformity.
Following medicines inspections, the manufacturer is required to identify the root cause of all deficiencies that are classified as either critical or major. Following devices inspections, manufacturers are required to identify the root cause for all nonconformities (both major and minor).
For each issue, the manufacturer's response should include action taken or proposed to be taken to correct the specific issue (including corrective action to prevent recurrence) and the completion date or, if relevant, target date for completion.
For deficiencies classified as critical or major (medicines inspections) and for all nonconformities (devices inspections) an identification of the root cause is also required. Where identification of the root cause is required, the response should include corrective action to the root cause as well as corrections to the individual examples identified.
deficiencies classified as critical or major (medicines inspections) as well as for nonconformities classified as major (devices inspections), objective evidence is required, e.g. copies of amended documentation, photographs etc.
The Lead Inspector provides the manufacturer with an e-copy of a close-out record, which can be used by the manufacturer to provide the response.
Use of this template is not compulsory for the manufacturer.
Time lines for close-out
Where the Inspection report is normally issued within approximately four weeks of the inspection, the initial response is requested within four weeks of the date of issue of the Inspection report. This allows the manufacturer a total of approximately eight weeks from the closing meeting to provide a response.
The response is normally reviewed within approximately two weeks after receipt, but this might vary depending on inspector's travel.
If a subsequent response is required, the manufacturer is given an additional two weeks response time.
If a deficiency/nonconformity is in the process of being addressed but further time is needed to fully implement the corrective actions, the Lead Inspector may determine that the inspection be closed out with a requirement for progress reporting. Examples of circumstances in which progress reporting may be appropriate include but are not limited to: generation of stability data, generation of validation data, facility or equipment refurbishment updates etc.
After all corrections and corrective actions have been accepted, the inspection is closed out by issuing a close-out letter. This letter refers to the correspondence regarding the corrections and corrective actions, indicates the final compliance rating assigned to the manufacturer as a conclusion to the inspection and refers to any proposed amendments to site authorisations or conditions. The compliance rating is used by the TGA as one of the parameters to determine the re-inspection frequency based on risk assessment. Like all inspection correspondence, the Inspection report is signed electronically and issued via email to the manufacturer.
In case of an initial inspection, a decision on licensing or certification is prepared after the close- out of the Inspection as described in the section licensing/certification process above. The same applies for inspections following applications for variation of a licence or certificate.
The Act includes provisions for regulatory action(s) in the case where a re-inspection demonstrates non-compliance of a licensed or certified manufacturer of therapeutic goods. A Licence to Manufacture may be revoked or suspended under the conditions outlined in Section 41 of the Act. For overseas medicine manufacturers, the GMP Certificate issued will be varied accordingly, particularly in relation to authorisations and conditions. A variation to the authorisations and conditions of a GMP Certificate will be reflected in the relevant GMP clearance(s). A GMP clearance may be cancelled if a manufacturer has contravened the authorisations provided by a certificate or breached a condition of a certificate.
Conformity Assessment Certificates may be suspended under the conditions outlined in Sections 41EM to 41EQ of the Act or revoked under the conditions outlined in Sections 41ER to 41EWQ of the Act.
All information relating to an inspection is treated as commercial-in-confidence information by the TGA and staff. At no time are the details of the inspection released to sponsors who may have requested the inspection. The information is considered to be confidential between the manufacturer on the application and the TGA.
However, section 61 of the Act provides for the Delegate to release details of the inspection to other authorities, for example the World Health Organization, an authority of the Commonwealth, a State or a Territory or to a regulatory authority of another country.
Fees and charges
All fees and charges associated with licensing/certification and conduct of inspections can be found on the TGA website.