Responding to a TGA Post Inspection Letter (PIL)
You have survived the TGA inspection and are now waiting for the arrival of the dreaded Post Inspection Letter (PIL).
Post inspection Letter
Following a GMP inspection, the TGA will issue a manufacturer with a PIL.
The PIL records any deficiencies identified during the inspection and categorises them as Critical, Major or Other. The deficiencies will reference specific clauses in the PIC/S Guide to Good Manufacturing Practice for Medicinal Products – Part I and/or II – PE 009 (the ‘Code’) to identify which compliance requirement was not met.
The contents of the PIL should only include deficiencies which are similar to, or the same as, the list of potential deficiencies that were included in the written Inspection Closing Meeting Summary (ICMS) provided at the closing meeting of the inspection. The ICMS is intended to make the manufacturer aware of the content of the forthcoming PIL.
If ‘new’ deficiencies that were not listed in the ICMS have been included in the PIL, the manufacturer should contact the Inspector to discuss the ‘new’ deficiencies; only potential deficiencies that were included in the ICMS should be included in a PIL.
In Addition to the PIL the Manufacturer will Receive a Close Out Record – How to Document the Response(s)
In addition to the PIL, the manufacturer will receive a Close Out Record (COR) as a Word document. The manufacturer is now expected to populate the COR (instructions given).
The format provided by the TGA is recommended for ease of review by the inspector. However, manufacturers can use a different format.
The supplied COR is simple to complete, there are headings for all the required areas requiring input i.e. you have clear and obvious prompts, and most importantly, the Inspector is familiar with the format which makes it easy for the Inspector to review your response.
The COR includes an instruction;
Cut and paste each deficiency from the Post Inspection Letter (PDF Document) into the table below. Ensure that each deficiency (for example, 1a, 1b, 1c, 2, 3a, 3b) is copied into a new row.
Interestingly, manufacturers often ignore the second part of the instruction Ensure that each deficiency (for example, 1a, 1b, 1c, 2, 3a, 3b) is copied into a new row. Typically, manufacturers copy one deficiency in it’s entirety per row even if there are multiple sub-deficiencies – Refer to Example 1.
Example 1 – One deficiency (including sub-deficiency) per row
In Example 1, the ‘Identified Root Cause(s)’ for Deficiency 1.a., 1.b. and 1.c. would be different. However, by documenting the root cause under one heading, only one root cause may be considered and documented, for example, a generic documentation root cause, that is not applicable to all the sub-deficiencies, or the depth of each individual root cause analysis may not be sufficiently robust.
From a practical perspective, even if multiple root causes are uniquely identified e.g. Root Cause to Deficiency 1.a., 1.b., 1.c. etc…..documenting them together under one heading is simply difficult to read and may lead to confusion. The lack of differentiation is further exacerbated when the Inspector’s review comments are included and may not align across the row, in particular, if all the responses are not accepted at the same time.
Whilst it is highly unlikely that an Inspector will return the COR to you and ask you to complete it as per the instruction, copying each sub-deficiency into a new row has it’s merits and is recommended – Refer to Example 2.
The documented response and subsequent Inspector review(s) are only applicable to one sub-deficiency at a time. This method will result in the COR increasing to what some manufacturers may consider to be an excessive number of pages; however, the author believes the proposed format will be make it easier for both the manufacturer and the Inspector to document and review the response(s). Concern over the number of pages in the final version of the COR should not dictate the format of a COR.
Example 2 – One sub-deficiency per row
A manufacturer will have two (2) opportunities to submit subsequent responses if the manufacturer’s first response is not accepted by the Inspector – Refer to Example 3. If the third response is not accepted by the Inspector, it is likely the inspection will be referred to a Review Panel.
Example 3 – How to document Responses 2 and 3 (if required)
Example 3 is the author’s preferred method for documenting subsequent responses. A new line, highlighted in color (any color may be used) is inserted each time a new response is required. The method is highly visible, highlights subsequent responses and enables an Inspector to quickly scroll down a COR and identify these responses i.e. there is no need for the Inspector to search through the entire COR searching for responses to deficiencies which have not yet been accepted.
The headings in the ‘Manufacturer’s Response’ column for subsequent responses should be customised to only include headings for which a response is required. For example, if the Inspector rejects the ‘Identified Root Cause’, then headings for ‘Corrective action/s to the Root Cause’ and ‘Preventative action/s to the Root Cause’ will also be required. However, if the ‘Identified Root Cause’ is accepted and the Inspector only requires an additional response to the ‘Corrective action/s to the Root Cause’, only this heading needs to be inserted.
Whilst a well formatted COR will not influence whether a response is accepted or not by the Inspector, a well-structured and clear COR will make it easier for the Inspector to review the responses.
‘New’ Deficiencies not listed on the ICMS
‘New’ deficiencies may be included in the PIL because either:
- An issue was discussed by the inspector during the inspection, but was accidentally omitted when the ICMS was generated.
- When reviewing their inspection notes, the Inspector realised an issue should have been raised with the manufacturer as a potential issue but was not.
If ‘new’ deficiencies were not discussed during an inspection, the manufacturer has been denied the opportunity to present additional information during the inspection to address any issues raised, i.e. the manufacturer has been denied natural justice.
The manufacturer should request that the deficiency is removed as it was not discussed during the inspection, but unfortunately, should be prepared for the Inspector to refuse to do so. At a minimum, the manufacturer should be allowed to discuss the issue and be given the opportunity to present the additional information which would have typically been presented during the inspection.
In both cases, as a courtesy, the Inspector should have contacted the manufacturer to discuss the inclusion of the ‘new’ deficiencies before they were included in the PIL.
Completing the Close Out Record
Manufacturers should review the TGA’s guidelines and requirements for closeout records – Refer to A step-by-step Guide to Addressing Deficiencies
Ensure that you understand what specific information and documentation are needed for the closeout process.
Critical and Major Deficiencies
An investigation of the root cause of all critical and major deficiencies is required.
Root Cause Analysis (RCA) is critical for determining the underlying causes of undesirable events within an organization. Tools such fishbone diagrams, cause-and-effect, 5-Whys (a favourite tool that is simple to use), processing mapping may be used.
Brainstorming is often used as a preliminary tool and then the information gathered is further critically evaluated and challenged. No suggestion/idea should be dismissed without evaluation.
If the initial findings are not adequately investigated to identify the root cause(s), the implemented Corrective and Preventive Actions (CAPA) may not fully address the underlying issues.
A detailed and robust RCA may identify some unpleasant truths as to how activities are be managed within an organization.
It is important to drill down and always dig deeper to find the true root cause of a problem. For example, if the root cause of a problem is identified as ‘Human error’ further investigation may identify ‘Inadequate training’, as a possible root cause. The investigation should go further and determine why training was inadequate.
If the TGA does not accept the identified root cause provided by the manufacturer, the TGA may will request a more thorough analysis to ensure that corrective actions are targeted at the core problems rather than just addressing surface-level symptoms.
Other Deficiencies
For Other deficiencies, the TGA does not require an investigation of the root cause.
Internally, it may be appropriate for a RCA to be conducted. However, the results of the RCA should not be included in the COR.
For Other deficiencies, only a ‘Correction to observed examples’ and a ‘Proposed completion date’ are required. The pharmaceutical equivalent of ‘War and Peace’ is not required when providing a response to an Other deficiency however, a brief explanation of the correction that will be implemented should be provided.
For example, if a deficiency is received for not describing a particular process XYZ in a procedure, the correction should not simply be ‘The procedure will updated’. A more appropriate response could be, ‘SOP XXX – Title, will be updated to include a section describing how process XYZ is managed’.
Objective Evidence
Unless requested to, the TGA no longer requires manufacturers to include objective evidence when completing a COR.
Provide a response to the entire Deficiency
Deficiencies often refer to multiple issues. Manufacturers must ensure their response addresses all point raised in a Deficiency. For example, in the example below four (4) unique issues have been described in one Deficiency.
‘The manufacturer used food-grade materials in the manufacture of Product X. However, there was no justification for the use of food-grade materials. In addition, there was no requirement for pre-acceptance testing to ensure the suitability of the materials. Example, Raw Material X used in Buffer X had not been risk assessed and/or tested for endotoxin including the food container used for sample collection.’
Disputing a Deficiency or asking for Clarification
All deficiencies are given based on the judgement of the Inspector. However, the Inspector is not always correct and may try to ‘encourage’ a manufacturer to implement a personal expectation rather than a Code requirement.
Be wary of comments the Inspector may make during an inspection. For example:
- ‘Don’t you think you should do XYZ’ rather than ‘You don’t do XYZ’. The former statement may infer that the Inspector wants a personal opinion implemented rather that a Code requirement.
- ‘l’m not sure what I don’t like, but l know l don’t like what l see’. If the Inspector cannot clearly articulate want the issue is, it is likely not supported by a Code requirement.
Manufacturers can and should ‘push-back’ on findings if they believe they are not supported by the Code. Push-backs should be done in a polite but firm manner. For example:
‘The Deficiency is acknowledged.
However, could the Inspector please clarify exactly which Clause or part of the Clause specifies that XYZ is a requirement’.
OR
If the manufacturer believes the incorrect clause was cited and there is no other appropriate clause the following question may be put to the inspector.
For example, the following is an actual example of a Major deficiency given to an API manufacturer in 2021. The manufacturer was cited for not having a Quality agreement with the supplier of a raw material; the raw material supplier had been qualified by the manufacturer. Clauses 16.12 and 2.21 of Part II of the Code were used to ‘support’ the deficiency. The question put to the Inspector demonstrated that the manufacturer was aware of it’s responsibilities and believed the clauses cited were incorrect.
‘The Deficiency is acknowledged.
However, Clause 16.12 is applicable to Contract Manufacturers (including laboratories) and Clause 2.21 relates to Quality Risk Management.
Clause 5.28 of Part I of the PIC/s Code of GMP states there should be a formal quality agreement or specification for starting materials.
It would be appreciated if the TGA could clarify, which Clause in Part II of the PIC/s Code of GMP states that a Supplier Agreement is required between XYZ and the manufacturers raw materials.
Deficiencies are often given for a lack of a procedure for a particular process. However, there should also be a specific Code requirement for what is being asked for. If there is no Code requirement, there is likely no need to have a procedure.
For example, the Code requires manufacturers to investigate customer complaints; there is an entire chapter dedicated to the management of customer complaints. However, if there was no requirement to manage customer complaints there would not be a need to have a procedure. This premise applies to all elements of the Code.
Manufacturers should not be afraid of challenging a deficiency during the Close Out process. However, the manufacturer must be prepared to back up their position with enough factual, objective evidence to be convincing.
If the Inspector is asked to clarify and/or explain why a particular clause of the Code has been cited, a written response by the Inspector should be provided. The manufacturer now has in writing exactly what the issue is and subsequent responses can be formulated with this information in hand.
In some case, the Inspector may choose to withdraw the deficiency.
There are no guarantees, but if manufacturers do not even attempt a push-back, the deficiency will have to be accepted however unpalatable or unjust it may seem.
‘But this has never been raised as an issue in the past’
Just because an issue has never been raised in the past, it doesn’t mean it is not an issue. IInspections are a snapshot and different Inspectors may not always look at exactly the same thing.
If a Deficiency can be supported by a clause in the Code, it is valid.
Inspection Feedback Form – Interpretation of Requirements
During an inspection, manufacturers occasionally, possibly more than occasionally, disagree with an Inspector’s interpretation of requirements. Despite presenting objective evidence to support their position, the Inspector may be immovable, and it is more than likely that a deficiency will eventuate.
At a point in time, the manufacturer should recognise that the Inspector will not change their opinion and cease trying to convince them to change their opinion. If not, the manufacturer runs the risk of ‘annoying’ (a possibly mild term to describe how the Inspector is feeling) the Inspector.
If a deficiency does eventuate, the manufacturer may submit an Inspection Feedback Form – Interpretation of Requirements. The form is intended for use when a manufacturer has a different view concerning the interpretation of the Code of GMP, an international standard, or demonstrating compliance with an Essential Principle made by an inspector(s).
You may feel that you are presenting the same information as was presented during the inspection but the information presented in the form will be reviewed by an independent reviewer who may not agree with Inspector.
In PharmOut’s experience, manufacturers are generally reluctant to submit the form to the TGA as they are concerned that they will be ‘back-marked’ by the TGA in future inspections.
However, manufacturer’s should note that the feedback received in this form will not be treated as a complaint by the TGA but will be used as a means of continuous improvement and to assess the consistency of inspector’s, interpretations and assist in training programs for inspectors.
PharmOut encourages manufacturers to submit an ‘Inspection Feedback Form – Interpretation of Requirements’ if appropriate. Contrary to popular belief, Inspectors are human and not always correct in their interpretation of the Code of GMP.
Inspection Feedback Form – Routine
The Inspection feedback form – Routine is generally considered to be a complaint form by manufacturers and which manufacturer’s are even more reluctant to submit. It should be noted that this form can be submitted to provide positive feedback about an inspection – it would be interesting to know if a manufacturer has ever provided positive feedback to the TGA about how an inspection was managed.
Conclusion
In summary, responding to a TGA PIL requires a strategic and transparent approach. By acknowledging the issues, providing a thorough analysis, and outlining effective corrective and preventive actions, manufacturers can navigate this challenging process and work towards achieving and maintaining compliance with regulatory standards.
How PharmOut can Help
Please contact PharmOut to enquire about our auditing services. We can facilitate both on-site and remote auditing, as well as provide recommendations and guidance on addressing and resolving your audit deficiencies.
