QP responsibilities

Question 1

Name the articles and directives where QP role has been defined in.

Answer 1

Article 48 of Directive 2001/83/EC

Vet:Article 52 of Directive 2001/82/EC

Question 2

Certification of the finished product batch- What does it represent?

Answer 2

The quality release of the batch before the is released for sale or distribution.

Question 3

Certification of the finished product batch; Name the relevant directives

Answer 3

Article 51 of 2001/83/EC

Vet: Article 55 of 2001/82/EC

Question 4

Annex 16, section 4 - The release of a Batch. Explain 3 main points

Answer 4

1. the stock can’t be released into sale before Quality Release. It should remain at the manufacturing site or be shipped under quarantine to an approved quarantine site.
2. There should be safeguards in place to prevent premature release into the market.
3. There should be a procedure covering on communicating QP certification to the site holding the stock and the certification needs to formal, written and clear.

Question 5

Annex 16- Chapter 3 Handling of unexpected deviations

What needs to have been met for QP to certificate a product with a deviation?

Answer 5

Registered specifications for APIs, excipients, packaging materials and medicinal products

Question 6

Annex 16- Chapter 3 Handling of unexpected deviations

a) How should the deviations be managed to allow batch certification?
b) what else should be considered before continuing manufacture of further batches

Answer 6

a) The deviation should be thoroughly investigated and the root cause corrected.
b) Submission of a variation to the MA

Question 7

Annex 16- Chapter 3 Handling of unexpected deviations
The deviation should be assessed following QRM principles. What 3 points should the process contain?

Answer 7

i. Assessment of the impact on the safety, quality and efficacy and a conclusion that the impact is negligible.
ii. Consideration of including the affected batches in on- going stability programme.
iii. biological products, changes in process could have unintended impacts

Question 8

Outline the general principles in Annex 16

Answer 8

“The ultimate responsibility for the performance of a medicinal product over its
lifetime, its safety, quality and efficacy, lies with the marketing authorisation
holder (MAH).
However, the QP is responsible for ensuring that each individual batch has been
manufactured and checked in compliance with laws in force in the Member
State where certification takes place, in accordance with the requirements of
the marketing authorisation (MA) and with Good Manufacturing Practice
(GMP).”

Question 9

Against what requirements does QP certify the quality of the batch?

Answer 9

A QP certifies that
* the quality of each batch
* is in compliance with the requirements
* of the law
* of the marketing authorization
* of the GMP Guidelines

Question 10

Name the duties QP must personally ensure?

Answer 10

certification is permitted under the terms of the
MIA
* any additional duties and requirements of national
legislation are complied with
* certification is recorded in a register or equivalent
document

Question 11

Name the responsibilities listed in Annex 16. point 1.7.1 to 1.7.4

Answer 11

1.7.1 all activities associated with manufacture have been conducted in accordance with the principles and guidelines of EU GMP
1.7.2 the entire supply chain of the active substance and medicinal product is documented and available for the QP
1.7.3 all audits of sites involved in the manufacture of the medicinal
products and in the manufacture of the active substance have been
carried out and the audit reports are available to the QP
performing the certification
1.7.4 all sites of manufacture, all manufacturing activities and the source and
specifications of starting material and packaging materials used are
compliant with the marketing authorisation

Question 12

Name the responsibilities listed in Annex 16. point 1.7.5 to 1.7.8

Answer 12

1.7.5 active substances have been manufactured in accordance with GMP and,
where required, distributed in accordance with GDP
1.7.6 excipients have been manufactured in accordance with appropriate GMP
(in the case of human drugs only, formalised risk assessment,
Guidelines 2015/C 95/02)
1.7.7 when relevant, the TSE status of all materials used in batch manufacture is
compliant with the terms of the marketing authorisation
1.7.8 all records are complete and endorsed by appropriate
personnel

Question 13

Name the responsibilities listed in Annex 16. point 1.7.9 to 1.7.12

Answer 13

1.7.9 all required in-process controls and checks have been made
1.7.10 all manufacturing and testing processes remain in the
validated state
1.7.11 personnel are trained and qualified as appropriate
1.7.12 finished product QC test data complies with the registered
specification

Question 14

Name the responsibilities listed in Annex 16. point 1.7.13 to 1.7.16

Answer 14

1.7.13 any post marketing commitments relating to manufacture of the
product have been addressed
1.7.14 on-going stability data continues to support certification
1.7.15 the impact of any change to product manufacturing has been
evaluated and any additional checks and tests are complete
1.7.16 all investigations pertaining to the batch being certified
(including out of specification and adverse trend investigations)
have been completed to a sufficient level to support
certification

Question 15

Name the responsibilities listed in Annex 16. point 1.7.17 to 1.7.21

Answer 15

1.7.17 any on-going complaints, investigations or recalls do not
negate the conditions for certification of the batch in
question
1.7.18 required technical agreements are in place
1.7.19 the self-inspection programme is active and current
1.7.20 appropriate arrangements for distribution and shipment
are in place
1.7.21 the safety features have been affixed to the packaging,
where appropriate

Question 16

Contract manufacture –
Role and duties of both QPs

Answer 16

There should be a clearly written technical agreement:
* delineating responsibilities of both QPs
* reviewed and approved by the contract giver’s and the
contract acceptor’s QP

Question 17

Role of Contracted QPs

Answer 17

There should be a written contract
* delineating the duties and responsibilities of the QP
* ensuring free access to any information, documentation, premises, procedures etc.
relevant to the decision-making processes when certifying batches
* defining the flow of information in the case of unusual events (e.g., deviations which
need to be considered in relation to batch certification)
* Contracted QPs should spend enough time for control and oversight

Question 18

CPD as professional duty

Answer 18

• QPs have a personal and professional duty to keep their knowledge and
  experience up to date: it is expected that this covers, inter alia, the current
  state of
• pharmaceutical quality management
• regulatory aspects
• GMP standards,
• product manufacturing and control technology

Question 19

Professional Conduct

Answer 19

QPs must ensure that
* senior company executives are made fully aware of any
difficulties:
* difficulties which may cast doubt on the certification of
batches or might require a product recall
* if there is any aspect of the Quality Assurance system which is
not in accordance with GMP standards, the QP has a duty to
bring this to the attention of Senior Management and ensure
that appropriate corrective measures are taken

Question 20

There are non-delegable duties

Answer 20

1) Ensure certification is permitted under the terms of the MIA/ManA/CTA

2) Ensure any additional requirements of national law have been met

3) Certify in a register that is maintained and available for inspection and up to date

Question 21

How many additional delegable duties is there? List the additional duties.

Answer 21

21 additional duties.

1.Manufacturing and testing are in accordance with GMP.

2. Supply chain available
   -Manufacturing (packaging, starting and critical materials)
   - Preferably a diagram
3. Audit of all sites involved in manufacture and testing plus AS manufacture. Reports available to QP.
4. All sites comply with the MA for the intended territory.
5. All manufacturing and testing comply with the MA for the intended territory.
6. Starting material spec and source compliant to MA. Supplier QMS in place.
7. For products subject to 2001/83/EC or 2001/82/EC the AS have been manufactured and shipped in compliance with GMP and GDP
8. Importation in compliance with Art 46b for 2001/83/EC
9. For products subject to 2001/83/EC excipients manufactured in compliance with GMP in Art 46f
10. TSE status compliant to MA
11. All records complete and endorsed by appropriate personnel. All in process checks have been made.
12. All processes in validated state and personnel are trained.
13. QC data complies with specification in MA.
14. Post marketing commitments have been addressed. On going stability supports certification
15. Impact of any change assessed and additional checks if needed are complete.
16. All investigations (including OOS and OOT) have been completed to a sufficient level.
17. Ongoing complaints/recalls/issue do not stop certification.
18. Required technical agreements are in place.
19. Self-inspection programme is active and current.
20. Agreements for shipment and distribution are in place.
21. Safety features in place where appropriate (Article 54o of 2001/83/EC)

Question 22

List the QP responsibilities related to the marketing authorisation (the MIA, ManA or CTA)

Answer 22

o Sites comply with MA

o Processes comply with MA

o Materials comply with MA (Site and Spec) / Supplier QMS in place

o Batch in Specification to MA

o TSE compliant if in MA

Question 23

List the QP responsibilities related to the site licencing.

Answer 23

o All sites (Manufacture/Test/AS) audited and reports available

o Self inspection is active and current

o All processes in validated state and personnel are trained.

o Supply chain available to QP

o Required technical agreements are in place

Question 24

List the QP responsibilities related to falsified medicines directives?

Answer 24

o AS complaint to GMP and GDP

o AS imported has written confirmation of GMP (if not on whitelist)

o Safety feature in place

o Agreement for dist and shipment in place.

o Excipients compliant to GMP

Question 25

What documents should be available for the QP at the time of the release?

Answer 25

The batch documentation pack – what the qp will see at the time of release;

o Manufacturing and testing are in accordance with GMP.

o All records complete and IP checks complete

o Post marketing commitments met, stability data supports investigation

o Any changes assessed and any needed checks completed

o All investigations complete to a sufficient level

o Nothing open that stops certification (complaint/recall etc)

Question 26

Name 1.7.1

Answer 26

1.7.1 all activities associated with manufacture have been conducted in accordance with the principles and guidelines of EU GMP

Question 27

Name 1.7.2

Answer 27

1.7.2 the entire supply chain of the active substance and medicinal product is documented and available for the QP

Question 28

Name 1.7.3

Answer 28

1.7.3 all audits of sites involved in the manufacture of the medicinal
products and in the manufacture of the active substance have been
carried out and the audit reports are available to the QP
performing the certification

Question 29

Name 1.7.4

Answer 29

1.7.4 all sites of manufacture, all manufacturing activities and the source and
specifications of starting material and packaging materials used are
compliant with the marketing authorisation

Question 30

IMP QP Responsibilities

Answer 30

contains minimum elements to be taken under consideration by QP’s during certification of IMP and additional ones may be required depending on product specific aspects:

1. Batch records, including control reports, in-process test reports and release reports demonstrating compliance with the product specification file, the order, protocol, and randomization code
2. All deviations or planned changes. In the case of an unexpected deviation during manufacturing process or inspection in relation to the details included in authorization, the QP may consider confirmation of compliance or batch certification if:
   i. The requirements of registered specifications are met for Active Pharmaceutical Ingredient (API), excipients, packaging materials and finished product
   ii. The deviation has been thoroughly investigated and the root cause remedied (a modification of the authorization may be necessary) and it has been confirmed that it has been included in the stability studies
   iii. The impact of the deviation has been assessed in accordance with the principles of QRM using the correct approach (assessing the potential impact of the deviation on the quality, safety, and efficacy of the product and demonstrating that this impact is negligible)
3. Production conditions
   The validation status of facilities, processes, and methods
4. Examination of finished packs
5. Where relevant, the results of any analyses or tests performed after importation
6. Stability reports
7. The source and verification of conditions of storage and shipment
8. Audit reports concerning the quality system of the manufacturer
9. Storage of retain and reference samples
10. The documents certifying that the manufacturer is authorized to manufacture investigational medicinal products or comparators for export by the appropriate authorities in the country of export
11. Where relevant, regulatory requirements for marketing authorization, GMP standards applicable and any official verification of GMP compliance
12. All other factors of which the QP is aware that are relevant to the quality of the batch

And remember… where IMP is manufactured and packaged at different sites under the supervision of different Qualified Persons, the recommendations listed in Annex 16 of Eudralex Volume 4 should be followed as applicable. Any sharing of responsibilities amongst QPs must be defined in a document formally agreed by all parties.