1. Quality Culture: what are the benefits for the shop floor?
If there is a good quality culture in place at a company, this can be seen at all levels. It is achieved because of a number of factors, including but not limited to the fact that all employees are valued and feel part of a team, they are listened to and their ideas considered, the processes or activities they are involved working with are reviewed to see how to make them better/easier/more efficient so it helps them be successful more often.
I personally don’t think this is just at shop floor level; and actually, often the greatest differences and improvements are seen in these areas as they were ignored and not valued previously.
2. Is Annex 21 applicable to import of Medicinal Products for use in a European clinical trial (as IMP, not for placing on the EU "market")?
Yes, since the legal basis for Annex 21 refers to e.g. Directive 2003/94/EC for medicinal products for human use and Directive 91/412/EEC for veterinary use.
3. Please, clarify what is meant by "clear and sufficiently detailed Job Description .... as well as the relationship to others”.
As per Chapter 2 EU GMP “people in responsible positions should have specific duties recorded in written job description…”. The requirement to clearly show relationship between responsible positions is described also in Chapter 2. To ensure that this is well organised, it is recommended to define this as an element in the Job Description of the QP in sufficient detail based on the specific situation in a company. It is essential that people in responsible positions have a job description which clearly documents for what the individual is responsible and accountable, so that there are no gaps in the organisation with respect to ownership of actions, This helps to prevent misunderstandings, especially when things go wrong. In the case of QPs, especially if there is more than one QP in the organisation, the Job Description should identify what each QP is primarily responsible for, and also include any reference to any delegated responsibilities. It should also include references to any joint responsibilities and any reporting or supervisory roles that the QP has.
4. How to get the management of a hospital to understand the general purpose of good quality management and the specific role of a QP? Hospitals are no pharma companies and do not have the same quality mindset despite the production of IMP's & large batches.
In situations where hospitals are manufacturing IMPs and large batches of medicinal products, they have to follow GMP-requirements and should have a similar focus on the patient and product quality as the key target of good quality management. To obtain a manufacturing authorisation (as described in Chapter 1 EU GMP) “there must be a comprehensively designed and correctly implemented Pharmaceutical Quality System incorporating Good Manufacturing Practice and Quality Risk Management.” The inspection by the Competent Authorities will challenge and assess appropriate implementation of GMP. In cases where the QP might not be able to certify a batch as being manufactured under appropriate GMP, such batch should not be certified.
5. “…and have total management support on all aspects relating to the strength, integrity, safety, purity and quality (SISPQ) to allow them to carryout their job correctly”. What is the source of this wording?
SISPQ was an acronym used in my company when I worked in industry. It was widely understood at the time, especially in the USA by both industry and authorities, to represent the key issues needed to be addressed to ensure compliance with the GMPs. Standing for Strength, Integrity (sometimes called Identity), Safety, Purity and Quality, but be careful in which order you use the Acronym as if using Purity, Identity, Safety, Strength and Quality can give the wrong meaning to compliance.
6. How confidential can be the local Authorities be contacted by a QP?
As mentioned during the presentation, as a QP you should maintain a good working relationship with your Competent Authority. You should be able to discuss serious issues at a kind of peer level. But be aware that you should not use relationship with your authority for consultancy-like questions; you as a QP are supposed to being able to make your decision.
7. A batch is released by the EU-QP. Then it is shipped to a non-EU country. Which tests have to be done and by whom at the arriving non-EU country?
This will depend on the regulations established in receiving country. Some might accept EU-testing; some might not.
8. §13AMG: for API of animal origin manufactured within EU, a release by QP in Germany is not necessary (since API is not imported). Can be the same applied for API (animal origin) manufactured in an MRA-country (i.e. Japan)?
From my knowledge only Germany requires QP-certification of animal-API batches imported from non-EU country (reference: AMWHV). If such an animal-API is manufactured in another EU-country and then just transferred to Germany no QP-certification is required. If you import from MRA-country to Germany you also need a QP-certification of the animal API-batch, because certification must be performed under EU-MIA (Manufacturing and Import Authorization). Even if MRA-country, the MRA-manufacturer does not own an EU-MIA.
9. How would you organize the cooperation when the MAH and the CMO are two different legal entities?
When two different organisations collaborate, the collaboration must be outlined in a contract defining responsibility split etc. For the safety part there is normally a SDEA (safety data exchange agreement) outlining what safety data are in question and how the exchange of data will take place.
10. What is the mission/ scope of the recall committee?
Tasks are:
- Take the decision whether to initiate a recall
- Challenge and approve the CAPA plan
- Challenge and endorse the communication plan
11. How do you deal with your French Affiliate where the "Pharmacien Responsable" is responsible of the recall in regards of National Health Authorities ANSM?
If the recall is affecting products in France, the "Pharmacien Responsable" will be promptly and properly informed by CCC, and will be asked to bring forward to ANSM the information and documents related to the case, according to what agreed upon by the Recall Committee.
12. Is a QPPV needed if the product is only meant for export outside EU?
QPPV is a role according to EU legislation, so a QPPV is not needed outside of EU, however, in most global PV legislation a similar role is described as a similar functional responsibility will be expected also outside of EU.
Questions on Annex 1
1. Regarding unidirectional flow: What are the recommendations for time separation (by a traffic light system)?
2.2 Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles to provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Where alternative approaches are used, these should be supported by appropriate rationales and risk assessment and should meet the intent of this Annex.
2. Can you explain a little bit more of negative pressure isolators?
Negative pressure isolators should be avoided. However, especially when working with CMR-Substances this might not be possible.
3. Chapter 6: hydraulic systems: could you please give an example?
6.21 Major items of equipment associated with hydraulic, heating and cooling systems, e.g. such as those associated with Blow-Fill-Seal equipment should, where possible, be located outside the filling room. Where they are located inside the filling room there should be appropriate controls to contain any spillage and/or cross contamination associated with the hydraulic system fluids. Hydraulic systems are often used for lifting and also are often found as pressure tools with Blow-Fill-Seal equipment.
4. Is there any plan to revise the "aseptic/sterile process" sections of the ATMP-Guideline and to align it with Annex 1?
Currently not.
5. If decided, based on a rationale, not to perform PUPSIT (for simple buffer not likely to mask filter flaws), would it then be normal practice to submit the rationale to the authorities for approval before initiating the production?
Most probably this has to be decided on a case by case basis. The document available is still a draft.
6. My colleagues from Manufacturing proposed the following cleaning approach of the floor in grade C and B when they are idle. Grade C: 1/week, Grade B: 1/month. Shouldn't Grade B be also 1/week?
Grade B cleaning should certainly be more frequent than Grade C. However, when idle things are different. I suggest a decision based on principles of QRM is what you should do in first instance and then implement a plan.
7. Should CCIT performed on every batch?
In general yes. Samples should be taken and checked for container closure integrity (CCI) using validated methods. The frequency of testing should be based on the knowledge and experience of the container closure system being used. A scientifically valid sampling plan should be utilized. The sample size should be based on information such as supplier approval, packaging component specifications and process knowledge. Remember: visual inspection alone is not considered as an acceptable integrity test method.
8. Should the MAH QP have access to the record mentioned (sterilization record), even though the manufacturing of the sterile product is outsourced to a CMO where the CMO QP is certifying the batch for partial manufacturing?
Of course Annex 1 won’t be in contradiction to Annex 16.
9. Is vial and stopper combination considered as “closed by fusion”?
The following examples are given for closed by fusion:
8.21 […]e.g. Blow-fill-seal (BFS), Form-Fill-Seal (FFS), Small and Large Volume Parenteral (SVP & LVP) bags, glass or plastic ampoules […]
→ vial and stopper combination is NOT considered as closed by fusion.
10. Will the "classic rooms" be allowed for a new built sterile areas or isolators and RABS are the only option?
The current draft is requesting 4.1 The manufacture of sterile products should be carried out in appropriate cleanrooms, […] → classical cleanrooms are still allowed.
11. Will be CCS a formal auditable document?
As the document(s) are requested by the current draft, CCS is considered as a formal auditable / inspectable document.
12. Are there any real changes made to the requirements in Annex 1 or is it more clarification and expansion of already stated requirements?
Both.
13. Regarding PUPSIT, most of the pharmaceutical Companies are not implementing it because it could induce additional risk for the product. Is it acceptable to justify it on a position paper? What’s your though?
Most probably this has to be decided on a case by case basis. The document available is still a draft.
14. Will the new version of Annex 1 also contain details about VHP sterilization?
VHP sterilization is mentioned as an example in 4.39 and 10.8.
15. What are your thoughts on oral vaccines manufactured as sterile products following Annex 1? Any waiver from Annex 1 could be acceptable ? (e.g. no visual inspection, no endotoxin testing, any other...?)
2.2 Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles to provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Where alternative approaches are used, these should be supported by appropriate rationales and risk assessment and should meet the intent of this Annex.
16. What do you propose to use as a documented QP evaluation of the impact of changes of the new annex, a gap assessment signed by the QP in charge? Or is a global update of the QMS sufficient?
Both of these approaches are good. I would add that a top level Change Control be opened to manage the various strands of activity and that it get closed when the strands are closed, also ensure you put a time limit on completion dates for the strands! Do not let the strands of activity drag on indefinitely. Timeliness is always key.
17. When you are a non-sterile manufacturer but using the principles of Annex 1, would you advise documenting the elements utilised in a position paper or inherently documented into QMS SOPs?
Both seems to make sense.
18. In a MA it is written, "filling has to be under Annex 1 class A conditions" However it isn't clear, if missing those should be handled as a deviation to the process or OOS related to the product (thus releasing the batch under an OOS), what do you think?
In general compliance with the MA is a legal requirement. However this is an equipment GMP matter not a release specification matter. I suggest a deviation is appropriate.
19. Is Annex 1 applicable to QC testing labs like sterility testing, micro lab? What is the concept?
Annex 1 concepts should be applied to sterility testing arrangements. It makes sense that the testing arrangements in terms of Air Quality are at least as good if not better than the manufacturing arrangements, otherwise we cannot argue that the test is more reliable than the manufacturing. I suggest Annex 1 is not applicable to other micro related tests such as TVC counting, MLT etc.
Questions to session “Relationship between Sponsor and IMP QP”
Disclaimer – Please note
The comments and/or answers cited in this text are a compilation of the collective opinions and experiences of the IMP group members prepared by the EQPA IMP Working Group.
While clearly this can be expected to be compliant with current regulations and useful as experience sharing – under no circumstances can it be interpreted as a regulatory requirement or reflecting official regulatory requirements or legislation.
Neither can any answers provided by individual members of the IMP QP Working Group Board be construed as reflecting specific company practices or policies followed or in place in their respective companies of employment. The information included may be subject to changes.
1. Can the sponsor be located in the US (big company where the clinical centralization with GMP connection is in the US)?
- Yes, global sponsor can be located outside the EU.
- However, in case of EU clinical trials, an EU legal representative is required located in the EU taking up the legal role for the sponsor in EU.
2. I like the scheme in the introduction. I am CMO IMP QP in Europe, the sponsor is the contract giver located in the UK.
Their QP is now requesting audit reports from testing site in the EU and UK, is that really needed?
- In the new arrangements the sponsor or legal representative will have to be based in the EU
- The QP in the UK can accept the certification of the EU QP, confirming that the original certification was completed. The EU QP certification step should include appropriate qualification of testing sites based on e.g. audit.
- Arrangement between the EU QP and UK QP should be defined in a QP-QP agreement where you can negotiate the responsibilities
- Sponsor QP might want to receive audit reports of non-EU sites as input for QP declaration.
3. How to organize the second step of the 2 steps release if it is an academic trial and hence the sponsor is not an organization but the Principal Investigator/doctor? How can you be sure as QP that second step has been done before use of IMP?
- Define clear roles and responsibilities in a sponsor – QP agreement.
- Alternatively, execution of the second step might be delegated to the IMP QP, then the QP has the full oversight. Ultimately, the sponsor remains responsible for the clinical trial.
4. Would it be considered acceptable to ship a bulk drug product to a CMO (hence another QP) for clinical packaging without either API/DS or the bulk drug product released?
- Quarantine shipment (in exceptional cases, not a standard practice).
- A process should be in place with a robust safeguarding system as a part of the QMS to prevent finished clinical trial material being inadvertently certified before completed API release.
- Minimum set of acceptance criteria for the IMP batch should be pre-defined for approval of a quarantine shipment (by a QP).
5. Is the sponsor release really needed to be performed by a registered QP? In my experience sponsors don't have their own QP?
- Refer to question #3.
- We understand this question to focus on the second step of the two-step-release procedure.
- There is no requirement that this step is done by a QP.
- Roles & responsibilities should be clearly described in a sponsor-QP agreement
6. If a manufacturer is delivering trial products for a trial which another company or physician (IIS) is the sponsor. Would you expect the contract to be between the QP and sponsor or between the manufacturer and the sponsor?
- Scenario 1: manufacturer and the sponsor, where QP to QP responsibility delineation is included within this agreement.
- Scenario 2: manufacturer and sponsor agreement + a QP to QP agreement – kept as separate agreements.
7. In scenario 3 - what if the releasing QP is subcontracted (so a third company on the top of the sponsor one and the manufacturer)? Anything specific to be added?
- Nothing specific to what was covered in scenarios 2, 3 & 4 of the presentation.
- The certifying QP (final batch certification step) takes the overall responsibility for the IMP. Agreements should be in place.
8. As "QP confirmation" is usually used for partial manufacturing steps. Would the IMP manufacturer's QP do the final batch certification if the sponsor does not perform further manufacturing steps?
- It is not unusual to combine sponsor QP and packaging & labelling (P&L) QP
- Sponsor-QP agreement should be in place to clearly describe roles & responsibilities and the P&L QP should have a broader view beyond the P&L related activities as he/she is now also taking up the sponsor QP responsibilities
9. What is the main difference between quality agreement and QP-QP agreement? What are the implications in terms of QP responsibilities in case there is a quality agreement between the Sponsor QP and the Manufacturer QP but not a QP-QP agreement?
- Set-up and structure of technical agreements may depend on the company’s philosophy.
- Scenarios have been seen where quality agreements and QP to QP agreements are implemented side by side.
- Integrative scenarios, the content of which covers all requirements are widely spread as well.
10. What would be the difference between a certificate of compliance and a certificate of confirmation?
- Certificate of compliance would include the four compliance statements – GMP, IMPD, Product Specification File and Quality Agreement, as defined per Annex 13.
- Certificate of confirmation might specify a few of these four but not all.
11. Does re-confirmation according to scenario 4 not automatically belong to scenario 3, otherwise a GMP QP cannot release the product (first GMP release of two-step procedure is only possible in accordance with contracts and IMPD)?
- If scenario 3 QP/CMO QP claims CONFIRMATION, this would state compliance with all four items: GMP, IMPD, PSF & Quality Agreement per Annex 13.
In some occassions:
- Or regulations are interpreted differently by Sponsor QP or Scenario 4 QP and this Scenario 4 QP might add that extra dimension to the release step.
- Or per Quality Agreement, only some of the four items are delegated to CMO QP, so Scenario 4 QP would cover the others (typically IMPD compliance).
Or CMO QP might only have partial insight in the IMPD.
12. Following scenario: manufacturing of bulk within EU, labelling and packaging outside of EU, sponsor outside of EU. How far is the responsibility of the QP from the manufacturing site within the EU?
- The responsibility scope is defined by the scope of the confirmation CoC, here bulk manufacturing step.
13. The MAH/Sponsor has delegated internally quality oversight of the CMOs to one of its affiliates in The Netherlands.
The CMO doing DP filling issues a QP confirmation for only the activities they performed (sterile filtration, filling and packaging) but does not take responsibility for the release testing at the other contract labs of the MAH/Sponsor. Should then MAH have a QP in Europe certifying for the entire manufacturing of DS, DP and testing prior to exporting this IMP or commercial product outside EU?
14. Can a contract manufacturer QP release bulk for packaging if the IMPD is still in development?
- Roles & responsibilities and more specifically responsibility for the regulatory compliance check should be described in the Quality Agreement/ Sponsor Agreement.
- Scenario described above would be one possible option ? contract giver/author of respective IMPD sections has to ensure, that the actual bulk manufacturing process is accurately reflected in the IMPD, a robust change control process is required.
15. Who is the product owner? Is it the same person as sponsor QP? What is the difference?
- Sponsor is the product owner. Sponsor’s QP is the QP who conducts relevant IMP QP duties or activities on behalf of the sponsor.
Sponsor’s QP is not the owner of the product.
- Sponsor QP is a delegate of the Sponsor to oversee the Product Quality, but Product Ownership includes much more than the GMP Product Quality (e.g. QPPV, regulatory, etc.).
16. Does every certifying QP (if more than one in a company) need to sign QP declaration or is one representative QP enough?
- Only one responsible QP can sign per product / batch. In some countries, e.g. Belgium, only one QP is registered on the license.
- Basis is an unambiguous responsibility delineation between multiple certifying QPs per site, this responsibility delineation should include back-up QP assignment/s in the event of absence of the responsible QP (vacation, sickness, etc.).
- The product/batch responsible QP or the single registered QP on the licence (BE) signs the QP declaration.
(back-up QP/s don‘t need to sign).
- Can have more than one QP certification option from two different companies (2 QP declaration as two different IMP licences)
- It is technically possible to register two Qualified Persons working under two MIAs certifying two different products for one clinical trial:
a) section D.9.2 of the Clinical Trial Application Form may be duplicated to assign QP responsibility per product.
b) Separate P.3.1. documents and with that separate QP declarations will be maintained per product signed by the respective responsible QP.
17. What is considered to be the real reason for IMP not needed to be fully analyzed?
- We assume this question focuses on the testing upon importation of IMPs.
- When IMPs are imported from third countries, analytical control in the Union shall not be mandatory.
Dir 2003/94/EC, Art.11(2), Commission Delegated Regulation (EU) 2017/1569, Art. 10 (3)
- Real reason? Only assumption … IMP supply chains are more „protected“ and of less interest in falsification.
18. Regarding importation of IMP's, is Switzerland considered as EU country or Third country?
- Switzerland is considered a third country.
- QP declaration is needed.
- MRA EU- Switzerland includes IMPs.
- Import certification by EU QP is required when importing IMP from Switzerland into EU
19. If the IMP imported into the EU, and you perform only a step of the process, not including batch release: is Annex 21 applicable?
- Annex 21 is still in draft.
- According to the current draft wording: yes.
20. For scenario 5 import of IMPs an ID check was mentioned (no complete testing). Does this refer to a chemical ID test?
- Yes (refer to ”Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigation medicinal products in clinical trials”, CHMP/QWP/185401/2004 final in EudraLex 10).
21. Does the MHRA guidance on import into UK apply to all types of IMP (DS, DP, FDP)?
- The Brexit related guidance applies to investigational medicinal products.
22. Who performs the final batch certification if the Sponsor has nor a MIA neither a QP? Missed that scenario. Sponsor could be a very small company?
- The sponsor would then need to work with a contract QP (under MIA) of another company.
- Possible scenarios: QP covering the last manufacturing step, e.g., CMO for packaging & labelling or a consultant QP working for the sponsor, or …
- The sponsor can outsource certification activities but needs a respective contract with the certifying QP.
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