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Live Online – Qualified Person Education Course & IMP Pre-Course Session

2-4 March 2021

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Q&As at the Live Online QP Forum 2020     

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General Questions

1. Quality Culture: what are the benefits for the shop floor?

If there is a good quality culture in place at a company, it does reduce frustration in employees and this is 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)?

TFrom 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?


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.

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