Pharmaceutical Quality Systems

Question 1

Supply chain scenario structure

Answer 1

1. Determine the Nature of the Question:
   Ascertain whether the query pertains to a standard process or involves complex challenges (CC).
2. Gather Product and Supply Chain Information:
   Identify product specifics, including:
   Controlled Drugs (necessitating a Home Office license).
   Biological products (subject to independent batch testing by national laboratories).

（SMLGC-AQT-WISPD)

3. Supply Chain MAP: Detailed visual representation outlining the flow of materials and products across all sites, from API manufacturing to final product distribution.
4. MA: Verify Inclusion of All Sites in the Marketing Authorization (MA): Ensure that every manufacturing, packaging, testing, and certification site is explicitly listed in the MA.
5. Confirm Authorizations, Licenses, and GMP Certifications:
   For each site, verify possession of appropriate credentials:
   API Site: Manufacturing authorization and, if applicable, API registration, CEP, ASMF, GMP.
   Manufacturing and Testing Sites: Manufacturing and Importation Authorization (MIA), GMP.
   Packaging Sites: Relevant authorizations for packaging operations, GMP.

QP Certification Site: MIA, GMP

Storage Facilities (optional): WDA (included in the Release site MIA)

Contract Lab for importation testing (optional): GMP cert (included in the Release site MIA)

6. QTA:
   Implement written agreements with all sites, clearly delineating responsibilities and ensuring adherence to GMP standards.
7. Audit Reports and QP Declarations:
   Obtain and assess recent audit reports for each site.
   Secure QP declarations for APIs and QP declarations for imported medicinal products (IMPs) from manufacturing sites, confirming GMP compliance.
8. Written Confirmation for APIs:
   For APIs sourced from third countries (outside UK/EU), acquire written confirmation from the competent authority of the exporting country, verifying GMP compliance equivalent to EU standards.
9. Importation Testing:
   If manufacturing occurs in third countries without a MRA, ensure importation testing is conducted within the UK/EU to confirm compliance with MA specifications. (include bulk; intermediate)
10. Sampling Arrangements:
    Establish procedures for:
    Representative Sampling: Ensuring samples accurately reflect the batch.
    Reference Samples: basically EU/UK site unless MRA (written agreement required)
    Retention Samples: Storage at the release site, in line with Annex 19 of the EU GMP Guide.
11. PQR arrangement:
    Schedule regular PQRs to evaluate the consistency of the manufacturing process and product quality across all sites.
12. Stability Programme (On-going): Ensure continuous stability testing is conducted, with data accessible to the QP to verify product integrity throughout its shelf life.

13.Documentation check:
Maintain and review essential documents, including:
- Batch records (copy).
- CoA.
- CoC.
- Temperature records during distribution.

Question 2

Supply Chain NSF method

Answer 2

1.

Question 3

Scenario 1: You work as a QP, manufacturing site changes from UK to Turkey, API site changes from EU to China.

Answer 3

0. Question regarding: Type of product, formulation, location of PKG, QC, Releasing sites, Storage site, Market)
1. CC open and impact assessment on Licence, GMP, and Patient
2. MA licence variation, Type 2 as API (but need discussion with regulatory affairs).
   2.1. Expect to see manufacturing licence from competent authorities (China and Turkey)
   2.2. EU GMP certificate or equivalent
   2.3. Audit reports and QP declaration for new API and mfg sites
   2.4. No written confirmation required (China-Turkey)
   2.5. expect to see importation testing at UK site, sampling, reference and retention sample storage location (UK), as Turkey not MRA).
   2.6. QTA in place
   3.API site specific
   3.1 CEP/ASMF
   3.2 technology/Analytical Method transfer (if any singing isn’t gap)
   3.3 Impuriry profile
   3.4 Nitorosaminrinrisk assessment
   3.5 Ongoing stability programme active
3. API-FG site specific
   4.1 technology/analytical method transfer
   4.2. New stability batch with new API

Question 4

Scenario2: API from India, manufactured and packed in Germany, stored and released in UK for UK market – what would you require?

Answer 4

0: PKG site? UK Release site has storage department? Type of product (CD/Biological)
1. Supply chain map
2. MA: all sites listed on the MA
3. Licence: appropreate mfg/testing licence from competent authorities
4. GMP: Each site has EU GMP or equivalent certificate
5. Written confirmation between India (non-white list) - Germany (EU)
6. Importation test: Not required as MRA
7. Audit reports for each aite available and QP dec for API
8. PQR accessible for QP for each site
9. Sampling inline with Annex 16; 21, reference sample at German QC (written agreement, QP accessible) site or UK MIA site, retention sample at UK release site as per annex 19.
10. On going stability study for api and finished product active
11. API site-CEP/ASMF, Risk assessment for Nitorosamin
12. QTA in place
13. Documents for daily QP duties- CoA, CoC, Temperatire log during transit, copy of batch documents available
MIA QP perspective; MA QP perspective; talk through the method transfer process; in depth conversation (impurities, method transfer, API registration, validations, key documents, licence variation etc.)

Question 5

Scenario2 follow up: What is an RPi – what would they require?

Answer 5

RPI- responsible person import. At WDA site, RPI is responsible for check imported commercial product has been certified by EU QP as well as check the transit condition.

Question 6

Scenario2 follow up: What the requirements of if product was being released for German market instead?

Answer 6

1. EU QP certification
2. FMD requirements: safety features(tamper evident and cerialisation) EU market

Question 7

Scenario2 follow up: Question regarding serialisation, if the batch was commissioned. Would I accept and release in regard to the WF?

Answer 7

No - UK FMD requirements have been repealed byWF 2024.
Thus the batch has to be quarantined until the batch is decommissioned by EU site through EMVS = European Medicines Verification System.

Question 8

Auditing a generics CMO – what would I review/ request prior to the audit?

Answer 8

Discuss SMF and PQR:
SMF, PQR, recent External audit reports, product lists for risk based approach for audit.

Question 9

What are the contents of a PQR?

Answer 9

Finished product - EU GMP chapter 1 (ICH Q7 for API)
Review/trending of
1. failed batches
2. IPC results and QC test
3. significant Deciations, OOS/OOT
4.Major change control
5. major CAPA and efrectiveness
6. Recall and complaints
7. MA, licence variations
8. utilities, equipment qualification
9. On-going stability programme
10 TA
11 quality of startingmatrial including packaging materials

Question 10

What are the contents of a SMF

Answer 10

1. Address
2. Product name
3. PQS
4. Facility and equipment
5. Personnel, organizational chart
6. Documentation
7. Manufacturing method, validation, cleaning
8. QC analytical method
9. Outsourced activities
10. Complaint and recall system
11. Self inspection programme
12. Appendix: contract lab, storage place

Question 11

What guidance would you use to audit?

Answer 11

For finished product:
EU GMP chapter 1-9
Annexes as per the formulation
PIC/S aid memories

For API:
ICH Q7

Question 12

Scenario3: API China, product India, packaging (primary and secondary) plus testing Germany. German site certifies for EU market. UK product sent to storage site – what do you need as a QP?

Answer 12

As part of my answer I mentioned that the German QP could certify and product could be brought into UK via WDA and RPI

0. Confirm Product type, formulation, UK release site
1. Supply chain map
2. List all sites inMA
3. All sites have appropriate manufacturing/Testing/Packaging/Release license from individual competent authority, such as MIA in German and UK and licence cover importation activity
4. All sites have EU. GMP or equivalent certificate
5. All sites audit report available and QP dec been done for API site
6. QTA for all sites in place
7. No written conformation required as API-MFG sites are India
8. Importation testing at German site and product import from India. No importation testing required at UK site as EU is approved country.
9. Sampling arrangement as annex 16 and 21, reference sample kept at German QC (with written agrement) or UK MIA site, retention sample at UK releasing site.
10. API site: CEP certificate, Nitrosamine risk assessment
11. Documents for daily QP duties: CoA, CoC, transport log, copy of batch documents for API; finished product batches.
12. Confirm UK product pkg without serialization/decommissioned
13. UK pkg with UK Only label in place
14. PQR arrangement
15. On going stability programmed for both API and FP

Question 13

Scenario3 follow up: What checks the RPI do?

Answer 13

When importing medicinal products from the EU into Great Britain, the Responsible Person (import) (RPi) must perform several critical checks to ensure compliance with UK regulations. These responsibilities are detailed in the MHRA’s guidance on acting as an RPi . 

Key checks include:
1. Verification of QP Certification:
• Confirm that each batch has been certified by a Qualified Person (QP) in accordance with Article 51 of Directive 2001/83/EC. 
• Acceptable evidence includes:
• A batch certificate confirming QP certification.
• A copy of the ‘control report’ as per EU GMP Annex 16.
• A statement of certification confirming compliance with Article 51.
• Documentation from internal systems indicating batch certification.
• Confirmation that the final manufacturing step was performed by an authorised manufacturer in a listed country.
• Verification that the medicine was purchased from an authorised wholesaler after being placed on the market in the listed country.
2. Independent Batch Release Certification for Biological Products:
• For biological medicines requiring independent batch release, ensure that a certificate from the National Institute for Biological Standards and Control (NIBSC) or a Mutual Recognition Agreement (MRA) partner is available. 
• Acceptable evidence includes:
• A statement from the marketing authorisation holder confirming batch certification by NIBSC or an MRA partner.
• A copy of the batch certificate issued by NIBSC or an MRA partner.
• Confirmation from NIBSC that a batch certificate has been issued.
3. Supply Chain Security:
• Ensure that the imported product:
• Is not subject to a recall.
• Has not been reported as stolen.
• Is available within the licensed supply chain of the listed country.
• Maintain compliance with Good Distribution Practice (GDP) requirements for supplier qualification as set out in GDP 5.2. 

Question 14

Scenario3 follow up: What would change if this was an IMP supply chain?

Answer 14

QP cert (Confirm batch certified in EU)
Supply chain (Confirm GMP & licence of manufacturing site
)
CTA & Ethics approval (Trial authorized; QP site matches CTA)
Written agreements (Sponsor-UK MIA(IMP), Sponsor-EU MIA(IMP), UK-Storage)
S (shipment/storage condition)
Reference Retention sample (written agreement must define in the Written agreement as well as timely access by MHRA )

When importing Investigational Medicinal Products (IMPs) into Great Britain from countries on the ‘approved country for import’ list (such as EU/EEA countries), the UK Manufacturing and Import Authorisation for IMPs (MIA(IMP)) holder must establish an oversight process to ensure compliance with UK regulations. This process is overseen by a Qualified Person (QP) and involves several critical checks: 
1. Verification of QP Certification:
* Confirm that each batch of IMP has been certified by a QP in the listed country before release for use in UK clinical trials. 
2. Supply Chain Documentation:
* Maintain comprehensive details of the manufacturing and distribution supply chain. 
* Ensure that the certifying site in the listed country holds the appropriate licenses and current Good Manufacturing Practice (GMP) certificates for the IMP dosage forms and associated activities. 
3. Clinical Trial Authorization Compliance:
* Have access to the UK clinical trial application form and any amendments to confirm the site responsible for final certification of the finished IMP. 
* Ensure that the clinical trial is authorized by the MHRA before the IMP is made available to investigators. 
4. Written Agreements:
* Establish clear written agreements outlining responsibilities and information provision between: 
* The sponsor and the UK MIA(IMP) holder responsible for import oversight.
* The sponsor and the listed country MIA(IMP) holder.
* The UK MIA(IMP) holder and any Great Britain storage and distribution hubs, if applicable.
5. Shipment and Storage Verification:
* Verify details of each IMP shipment to Great Britain, including recipient information, ensuring shipments are only made to approved trial sites as detailed in the UK trial application. 
* Review any deviations from stated storage conditions during shipment, along with decisions and rationales provided by the sponsor and certifying QP. 
6. Reference and Retention Samples:
* While additional samples are not specifically required to be stored in Great Britain, their storage location should be documented and accessible to the QP named on the UK MIA(IMP).

Question 15

Scenario3 follow up: If the storage site had its own WDA would it also need to be listed on your license?

Answer 15

Short Answer (for QP Viva):

Yes — if the storage site is involved in QP certification (e.g. storing uncertified product prior to QP release), it must be listed on the MIA.
If the batch is already QP certified in the EU, and the UK storage site is only storing certified finished goods, then a WDA(H) is sufficient and the site does not need to be listed on the MIA.

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Detailed Explanation:

1. When must a storage site be listed on the MIA?

Per MHRA guidance and EudraLex Volume 4, a storage site must be listed on the MIA if it:
• Stores uncertified product (i.e. before QP certification)
• Forms part of the GMP chain
• Is used as part of QP certification/release activities

If the site is performing GMP-related functions (e.g. holding IMPs or finished goods prior to certification), it must be listed on the MIA/MIA(IMP).

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2. When is a WDA(H) sufficient?

If the site is:
• Only storing QP-certified (released) commercial product
• Only distributing released product within the UK
• Not involved in QP release or any manufacturing/testing

Then a WDA(H) is sufficient, and the site does not need to be listed on your MIA.

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MHRA Guidance References:

a. MHRA Guidance – ‘Guidance for Importers’ (QP Oversight model)

“If a site is used for the storage of uncertified batches, it must be listed on the MIA and covered by the QP certification process.”

b. MHRA GDP and GMP guidance (2021–2023 updates):

“If a storage facility is used as part of the GMP supply chain for certification purposes, it must be included on the MIA. Storage of released product under WDA(H) does not require inclusion on the MIA.”

c. EU GMP Annex 16 (Section 1.5):

“The QP should have access to all relevant records and sites involved in batch processing and storage prior to certification.”

Question 16

R & D site moving to your MIA site. What is your concern? follow up: Thinking about the storage site – what would you expect of a PQS for WDA?

Answer 16

1. CC open
2. Description of change and identify facility/equipment to share
3. Risk assessment with ICH Q9
4. Impact assessment for licence. GMP and patient ( product)
5. Contamination control strategy and mitigation actions, such as segregation, effectiveness check.

Follow up question:
1. QMS (deviation, RCA, CAPA, cc system)
2. Personnel (organizational chart, training program etc)
3. Storage place enough capacity, not sorted on the floor, clean and tidy, temperature monitoring in place, PPM for facility and equipment in place
4. Documentation control (version control, senior approval)
5. Suppler/customer authorization system in place.
6. Recall/customer complaint system in place
7. Self inspection program active and current

Question 17

Scenario 4: API in Brazil, Bulk manufactured in Japan, Packed and Release in UK. Will you consider accepting the bulk testing for your release.

Answer 17

0. QC testing site? Type of Med (IMP/CD/Biological)? Formulation (as Japan is MRA, if within SCOPE?)?
   1.Confirm Supply Chain Map (BRZ white, JP MRA)
1. All sites are listed in the MA
2. All sites have appropriate licence for the activities
3. All sites have EU GMP or equivariant
   5.All sites QTA in place
4. All site Audit Report available
5. QP dec been done for API in BRZ
6. WC not required as API white list & not UK imported
7. Importation Testing for Bulk not required as Japan is MRA country (If within MRA scope).
8. Confirm sampling represent of the whole batch, reference sample can be stored in Japan (MRA) but need written agreement, and Retention sample kept at Releasing site (UK).
9. Additional document check: API site - CEP/ASMF, Nitrosamine risk assessment
10. PQR arrangement (API&FP)
11. On-going Stability Test
12. Documents for QP routine check: CoA, Temperature Log, Copy of Batch documents for API & FP
13. Other Delegatable Duties: TSE, PQS etc

Question 18

Scenario 4 follow up: What is the MRA with Japan?
what are the products excluded for batch testing acceptability from Israel?
What about the other countries?

Answer 18

JAPAN: Can omit importation testing excluding ATMP, Medical Gas, Human Blood
ISRAEL: Medical Gas, Homeopathic, Blood, ATMP

• Australia
  Advanced Therapy Medicinal Products
• Canada
  Medicinal products derived from human blood or blood plasma
  Advanced Therapy Medicinal Products
• Israel
  Medicinal gases
  Homeopathic products
  Medicinal products derived from human blood or blood plasma
  Advanced Therapy Medicinal Products
• Japan
  Medicinal gases
  Medicinal products derived from human blood or blood plasma
  Advanced Therapy Medicinal Products
• New Zealand
  Advanced Therapy Medicinal Products
• United States of America
  Vaccines
  Advanced Therapy Medicinal Products
  Medicinal products derived from human blood or blood plasma

Question 19

Scenario 5: API in China, Bulk manufactured in Spain, Bulk packed and released in NI.
You are a virtual QP, please tell me what you need in place to certify the batch?

Answer 19

0:type of product (CD/Biological/IMP)? QC site?
Market?
1. Supply Chain Map to ensure location - APi (3rd), Bulk&Test(EU), pkg&release(uk)
2. those sites listed MA
3. All sites have appropreate licence and cover the mfg, testing and importation activities for the product
4. All sites have GMP cert or equivalent
5. Audit reports available
6. QP dec has done for APi aite
6.1 CEP/ASMF, Nitrosamine risk assessment
7. QTA in place for all aite
8. Writren conformation with each API batch
9. No importation testing required as bulk importing from EU (approved country)
10. Sampling arrangement, reference sample spn (written agreement) or NI site and retention sample at NI site.
11. PQR arrangement
12. On going stability study
13. If exported EU, WDA listenrelease aite MIA + EU QP eligibility +FMD requirements. If UK market, UK only label.
14. Secure IT system ensure QP access to all information for QP certification such as coa for api and FP, transportation temperature log, copy of batch records
15. Ensure system for remote certification such as sop, staff training, define the process of QP release register, control measure to prevent product released without qp release as per MHRA inspectrate blog and annex 16.
16. Ensure QP physically site visit regularly.

Question 20

Scenario 5 follow up: Where would you find guidance on QP remote certification?

Answer 20

MHRA inspectrate blog

Question 21

Scenario 5 follow up: Your company has sourced a second API supplier, now based in Brazil. What do you do?

Answer 21

1.CC open
2. Impact:
- Licence variation for MA - type 2 confirming regulatory affairs
- check the api supplier has appropreate api registration.
Check CEP cer
3. GMP impact: GMP cert or equivalent
4. Audit and qp declaration
5.Nitrosamin risk assessment
6. No written confirmation required as BRZ whitel list
7. Put new batch on - going stability programme woth the new API

Question 22

Scenario 5 follow up: You have been notified that your API supplier has changed their solvent in their manufacturing process. What are your concerns?

Answer 22

0:
-was it controlled by CC? Was the change notified in advance as per QTA? - do we have batch with the new API at our site or already released? If any at aite, quarantine.
- any impact on MA , need variation?
-What is class of the solvent as in ICH Q3C?
- impurity profile?
- stability data any different?
- nitrosamineisk asseent done?
- impact on finished product - any difference + need our new bacth with the new solvent API?

1. Change Control Management
   • Confirm that the change has been handled under a formal change control by the API manufacturer.
   • Check whether you were notified through the QTA (if in place).
   • Evaluate whether the change has been communicated to the MAH and whether regulatory variation is required.

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2. Solvent Classification (ICH Q3C)
   • Identify the new solvent and classify it under ICH Q3C:
   • Class 1: Known carcinogens — typically not acceptable
   • Class 2: Toxic solvents — require tight control
   • Class 3: Low toxic potential — less impact
   • Assess whether residual solvent limits need to be updated in the API specification.

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3. Impurity Profile and Control
   • Has the solvent change affected the impurity profile?
   • Check for new impurities, higher levels, or solvent-related degradants.
   • Review analytical data and updated CoAs.
   • Confirm if method revalidation was required or performed.

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4. Stability Data
   • Assess whether the change impacts API stability.
   • Request comparative stability data before and after the solvent change, especially if the new solvent has different reactivity or volatility.

⸻

5. Impact on Finished Product
   • Determine whether the change could impact the critical quality attributes (CQAs) of the finished product.
   • Assess potential downstream effects on:
   • Dissolution
   • Assay/potency
   • Appearance or degradation profile
   • Check if finished product re-validation or equivalence studies are needed.

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6. Regulatory Filing Impact
   • Confirm if the change is considered a variation under the Marketing Authorisation (MA).
   • Likely a Type IB or II, depending on risk
   • Work with regulatory affairs to submit variation if required.

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7. QP Certification Readiness
   • Ensure full visibility of:
   • Change control documentation
   • Updated specifications and methods
   • Stability and impurity data
   • Only certify affected batches when satisfied that product quality is not compromised.

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Final Viva Statement:

“This type of change would trigger a detailed quality and regulatory review. As QP, I would assess the solvent classification under ICH Q3C, its impact on the impurity profile, residual solvent levels, API stability, and any downstream effect on the finished product. I’d verify that the change was controlled via change control, reviewed under the QTA, and determine whether regulatory variation is required. I would only certify the batch once I am confident that the change does not compromise product quality or regulatory compliance.”

Question 23

Scenario 6: You make antibiotic API in China, bulk manufacture, packaged and QC tested in USA, GB for certification for release to UK. As a QP what do you need to have in place to feel comfortable to certify?

Answer 23

0: product type:(CD/biologics/IMP)
1. Supply chain map (api: 3rd, mfg;pkg; qc: MRA), release: UK for UK market
2. All sites listed in MA
3. all sites have appropreate licence, registration and cover mfg, testing, packaging, release. Importation activities.
4. All sites have GMP or equivalent
5. Audit report available for all sites and QP dec completed
6. CEP cert/ASMF for API site and nitrosamin risk Assessment for API and FP sites.
7 QTA in place in all sites
8. No written confirmation as api not imported to uk
9.no importation testing as USA MRA
10. PQR available (api and fp)
11. On going stability study
12. Sampling arrangement. Reference sample at USA with written agreement, retention sample at releasing site UK.
13. Documents for daily qp duties- coa, temp log, copy of batch documents

Question 24

Scenario 6 follow up: API now changes to a site in India, what do you now need?

Answer 24

1. CC open
2. Impact on licence: MA variation type 2 (confirm with regulatory affairs)
3. Check new api site has appropreate licence for manufacturing, CEP cert
4. Impact on GMP - new site has GMP or equivalent cert, audit report, PQR/recent external audit result, and qp declaration
5. Impact on finished product:
   Impurity profile.Nitrosamine risk assessment, sptability study, put new FP batch on-going stability study woth th Rene API batch
6. QTA in place

Question 25

Scenario 6 follow up: You are manufacturing the API in China and you want to outsource. What do you need as a QP?

Answer 25

1. Open cc 2. Impact on MA: ma variation (type 2 confined byregukatiey affair) 3. Check the cmo has appropreate licence to cover the api manufacturing and testing 4. Check GMP certificate or equivalent 5. Check CEP 6. Audit as per ICH Q7 and QP dec 7. Check if written confirmation required (3rd country - UK/EU) 8. Impact on finished product: impurity profile, relevant use, synthesis passway, nitrosamin risk assessment, ongoing stability study 9. QTA in place 10. Supply chain map update 11. Put new fd batch woth the new api for on going stability study

Question 26

Scenario 6 follow up: What about a QTA and what are key things you need?

Answer 26

- Retention and reference samples (who take samples? if 3rd, need technical justification including 1. audit to ensure samples are representative of the batch 2. Scientific study including description of sampling, description of transport condition of sample and batch, comparative study 3rd vs after importation, consider time interval between sampling and importation of the batch and generation of data support appropriate defined time. - How deviations, OOS/OOT results, changes, CAPA and complaints are communicated. - Defined timelines for notification. - QP access to documentation (audit reports, PQRs, stability data, etc.) - Process for handling regulatory variations (e.g. MA changes). - Auditing & Review Audit rights and frequency - Access to third-party audit reports - Periodic review meetings or KPIs

Question 27

Scenario 7 – explain the requirements: * API – China * Bulk – Siberia * Packaging – Northern Ireland * Certification – England * Market – UK/EU

Answer 27

0. what type of product (CD, IMP, biological)? Market for EU cannot be certified - need EU QP arrangement at NI/EU site 1. Supply chain map (API: 3rd, Bulk: 3rd, PKG: UK, Certification: UK for UK market) 2. MA: all sites listed 3. Licence: all sites have appropriate licence to cover the MFG, Testing, PKG certification ,and importation activities 4. GMP or equivalent certificate 5. Audit repots available for all sites and QP dec for API site completed 6. No Written Confirmation required (china-Siberia) 7. Importation testing for Bulk from Siberia need conducted at NI site (i.e. Testing facility; GMP certificate, under NI MIA licence list) 8. Additional documents to check: CEP/ASMF at API site, Nitrosamine risk assessment 9. QTA with all sites 10. PQR access arrangement for API and FP sites 11. On going stability study active on API and FP 12. Control measure to prevent MIXUP batch for EU and UK 13. PKG FMD requirements for EU, UK ONLY label for UK batch 14. Documents for daily QP release: CoA, CoC, Copy of Batch documents for API and FP, making sure all OOS/OOT, Dev investigation completed, CC no negative impact on the batches.

Question 28

Scenario 8: Commercial product – API manufactured in India, Nasal spray primary packaged in the UK, secondary packaged in Spain, Tested and Certified in the UK, for the French market and also for a non-EU country. What would you need to see in place?

Answer 28

0: Product type (CD, IMP, Biological), at Spain site need QC test + EU QP certification for batch for EU market. UK QP for only UK/non-EU country market. Where is the Non-EU market? MRA countries? 1. Supplier market: API 3rd, Bulk 3rd, PKG EU, QC test and QP certificate for UK market/Non-EU market 2. MA: all sites list on MA 3. Licence: all sites have appropriate licence for manufacturing, testing, pkg, release and importation 4. GMP or equivalent 5. Audit reports for all site available and QP dec complete for API site 6. No written confirmation required and API batch not directly imported to EU/UK 7. Importation testing required at UK, Spain 8. CEP/ASMF, risk assessment for Nitrosamine at API and FP sites 8.1. Sampling arrangement - if sample taken India mfg site, Written agreement required covering description of sampling ensure sample represent of the batch scientifically, comparable study India vs Uk site, consideration of time interval between sampling and export as per annex 16. 8.2. reference sample at UK QC site, retention sample at Release site as per annex 19. 9. QTA in place with all sites 10. Arrangement for PQR access for API and FP sites 11. On-going stability programme 12. Documents for daily QP release: CoA, CoC, copy of Batch documentations for API and FP, ensure OOS/OOT, dev investigation completed, CC has no negative impact on the batches

Question 29

Scenario 8 follow up: Can the non-EU country accept your testing and certification?

Answer 29

If MRA country such as Japan, Israel, USA, Switzerland, Canada, Australia, Newzeland then they accept testing.

Question 30

Scenario 8 follow up: What would you consider for excipients?

Answer 30

As per annex 16, risk assessment required for ensuring GMP grade.

Question 31

Scenario 8 follow up: What do you know about nitrosamines?

Answer 31

Carcinogenic substance may cause cancer if taken long term. Nitrosamine can be synthesised during API/FD manufacturing. MAH has responsibility to conduct review their manufacturing processes to identify and, if found, to mitigate the risk of nitrosamine impurities being present, as per EC 726/2004.

Question 32

Scenario 9: API - India Manufacturing/ testing / packaging / certification - UK Market UK and EU As a QP what concerns would you have over this supply chain.?

Answer 32

0: Product type (CD/Biological/IMP)? UK QP only responsible for UK market. For EU batch needs EU QP certification (+ importation testing at EU) 1. Supplier Map (India non-white list country/Non-MRA country) 2. ALL sites (manufacturing, testing, PKG and Release) have appropriate licence to cover the activities) 3. All sites have GMP or equivalent cert 4. Audit reports available for all sites and QP de completed for India Site 6. Written conformation required for each API batch importing from India to UK 7. Importation testing not required as MFG-PKG-Certification in the UK 8. Sampling arrangement, reference; retention sample location defined in QTA/Written agreement 9. QTA in place 10. PQR arrangement for API and FP sites 11. On going stability study 12. API site - CEP/ASMF 13 Risk assessment for Nitrosamine for API and FP site 14. Documents for daily QP release - CoA, CoC, Copy of batch record 15. How to access QPPV and location

Question 33

Scenario 9 follow up: Can you talk to us about the differences between UK and EU importation?

Answer 33

Due to Brexit, EU sees Uk as 3rd country but UK still recognise EU as MRA country. This means Uk product imported to EU needs importation testing as well as EU QP certificate at EU MIA site, while EU product certified by EU QP can accept by WDA holder and RPI oversight.

Question 34

Scenario 10: API India. You are MIA/MAH in UK. Going to change UK mfg to India mfg (CMO). How?

Answer 34

1. Open CC 2. Impact on MA: variation - type 2 but need clarification with regulatory affairs 3. Impact on Licence - CMO has appropriate licence for manufacturing; testing. CEP certificate/ASMF 4. GMP certificate Written confirmation from Chinaese authotrities if API UK/EU imported. Audit report with ICH Q7 and QP dec 5. FP impact - Impurity profile, Nitrosamine risk assessment, ongoing stability programme, new batch with new API for FP onp=going stability programme 6. QTA in place, arrange for access to PQR 7. Update supply chain map

Question 35

Scenario 11: API site is moving from UK to India. Finished product site is moving from UK to South Africa. What documents would you require and how would you manage this change?

Answer 35

1. CC open 2.confirm that API India not white list country. South Africa is not MRA country 3. Impact on MA - variation for change (need Regulatory Affiairs clarification) 4. Impact on Licence - has new API site & FP site appropriate licence to cover the manufacturing/testing/importation activities? 5. GMP impact - EU GMP certificate or equivalent. Audit reports and QP declaration for both API and FP sites. No Written confirmation required between India-Sounth Africa Importation testing required between South Africa - UK. Sampling arrangement - who took sample? if South Africa does, sapling must represent the batch scientifically, comparable study South Africa vs Uk, commiseration around time interval between sampling and importation as in Annex 16. FP site: Technology; analytical method transfer for FP site, risk assessment for nitrosamine, on-going stability study API site: CEP, risk assessment for Nitrosamine, Impunity profile, on-going stability study QTA in place. PQR arrangement for API and FP sites. Up date supply chain map.

Question 36

Scenario 12: Finished product comes from South Africa to a 3rd party warehouse Distribution in UK and QP certification in UK. Who will take the samples, and what is the difference between Reference and Retention. What is WDA? How you hold it? (Supply chain question -> PQS+ API )

Question 37

Scenario 12 follow up: What is WDA? How you hold it?

Answer 37

WDA stands for Wholesale Dealer’s Authorisation. It is a legal licence issued by the MHRA in the UK (or national competent authority in EU), which permits a company to procure, store, distribute, or export medicinal products in accordance with Good Distribution Practice (GDP). There are two main types in the UK: WDA(H) – for human medicines WDA(V) – for veterinary medicines How do you “hold” a WDA? To “hold” a WDA means your organisation: 1. Has applied for and been granted the authorisation by the MHRA. 2. Maintains compliance with GDP, ensuring that: -Only authorised medicinal products are handled. -Products are stored and transported under appropriate conditions. -The supply chain is secure, traceable, and auditable. 3. Has a named Responsible Person (RP) on the licence who: - Ensures compliance with GDP. - Oversees the qualification of suppliers and customers. - Is responsible for handling complaints, returns, and recalls. - Maintains quality systems (e.g. training, deviation management, self-inspections). 4. Ensures premises, equipment, and documentation meet GDP expectations (as per EU GDP Guidelines – 2013/C 343/01).

Question 38

What would you check when auditing a WDA holder?

Answer 38

- PQS (Dev, CAPA, CC, self inspection etc) -Bona fide checks of suppliers/customers - Temperature monitoring - GDP training - Transport validation - Recall capability - Documentation retention (minimum 5 years)

Question 39

Scenario 12 follow up: What things would you consider when going for a new API source?

Answer 39

1. CC open 2. MA impact - variation (type 2 but conform with regulatory affairs) 3. Licence (appropriate licence, API registration) 4. GMP cert or equivalent, 5. Audit report and QP declaration 6. consider Written Conformation if API batch directory imported to UK/EU 7. Traceability, transport/storage condition, recall/customer complaint handle 8. CEP/ASMF 9. Risk assessment for Nitrosamine, impurity profile 10. QTA in place 11. PQR access 12. Ongoing stability programme 13. Supply chain Map

Question 40

Scenario 12 follow up: What I would consider to bring a new API from India?

Answer 40

- Bonafide check - Supply chain Map, confirming India is non-white list country - Appropriate manufacturing authorisation (licence) in place- Adult (in line with ICHQ7) and QP declaration - UK MIA site licence cover importation activity - Written confirmation if directly importing from India to UK - QTA in place - PQR arrangement - On going stability programme - New on-going stability batch for FP with the new API batch

Question 41

Scenario 12 follow up: API QP declaration -Whether you QP needed to be the one doing the audit?

Answer 41

No - as per EU GMP annex 16 says I can rely on 3rd party as long as the 3rd party has been approved through supplier authorise process to ensure their GMP audit competency. The audit has to be done in line with ICH Q7 and report available and approved by the QP.

Question 42

Scenario 12 follow up: Impurity profile - What do you understand by the impurity profile of API?

Answer 42

The impurity profile of an API refers to the types and levels of impurities present in the API, including: - Process-related impurities (from synthesis) - Degradation products - Residual solvents (as per ICH Q3C) - Elemental impurities (ICH Q3D) from Catalysts (e.g. platinum), reactor vessel (e.g. stainless), raw materials (e.g. calcium carbonate), water or environmental contamination - Genotoxic impurities (ICH M7) nitrosamine For a new API batch, I would compare the impurity profile against the approved specification in the MA/CTA and the toxicological limits defined in the relevant ICH guidelines.

Question 43

Any impurities that have been in discussion lately?

Answer 43

Nitrosamine: - Found in Sartans, Ranitidine, Metformin, rifampicin - Required control strategy per EMA & MHRA guidance

Question 44

Scenario 12 follow up: What would be the responsibilities of the API manufacturer for the control of nitrosamines?

Answer 44

As per EC 726/2004, ICH M7, MHRA guidance Marketing Authorisation Holders' submission of Nitrosamine risk evaluation, risk assessment and confirmatory testing'. 1. Risk assessment in the API process 2. Risk mitigation action 3. Communicate with MAH

Question 45

Scenario 12 follow up: What would be my responsibilities as the MAH on controlling nitrosamines?

Answer 45

As per EC 726/2004, ICH M7, MHRA guidance Marketing Authorisation Holders' submission of Nitrosamine risk evaluation, risk assessment and confirmatory testing' 1. Comprehensive risk assessment: API synthetic route, formulation, excipients, packaging materials, storage condition 2. Risk mitigation action: changing synthetic route, reformulation, change packaging material 3. MA Variation 4. On-going Monitoring

Question 46

Tell us different types of process validation

Answer 46

1. Prospective Validation (Traditional Validation) When: - Before routine commercial manufacture starts - New product or process Key Features: - Conducted on validation batches (usually 3 consecutive) - Based on a pre-approved protocol - Batches are not released until validation is complete 2. Concurrent Validation When: - There’s an urgent need to release product before full validation data is available - E.g. rare/orphan drugs, clinical supply, product shortages Key Features: - Conducted during routine production - Real-time monitoring and risk-based justification required - Batches may be released before validation is completed, if justified 3. Retrospective Validation (Legacy only) When: - Based on review of historical batch data - Only acceptable for legacy products (validated before current Annex 15) Key Features: - Involves statistical analysis of past batches - No longer acceptable for new products - Still relevant during inspections for older products 4. Continuous Process Verification (CPV) (Lifecycle approach) When: - Used as part of ongoing process validation - Often applied to complex, modern processes (e.g. PAT, QbD) Key Features: - Relies on real-time data collection and analysis - Supports real-time release testing (RTRT) - Integrated into ICH Q8–Q10 principles

Question 47

Scenario 13: When I got to pilot batch/validation batches, asked me how I would validate it, whether I would use concurrent validation or prospective?

Answer 47

“It depends on the purpose of the batch and the stage of product development. In most cases, I would use prospective validation for pilot or validation batches, especially when establishing a commercial manufacturing process before routine production. 1. Prospective Validation Definition: Validation is completed before routine commercial manufacturing starts. Used when: New product or process is being scaled up (e.g. pilot scale → commercial) You’re performing process validation batches (often 3 consecutive successful batches) Aligns with Annex 15 and ICH Q8–Q10 principles. 2. Concurrent Validation Definition: Performed during routine production, with real-time monitoring. Used when: There is limited historical data (e.g. rare disease, low-volume product) Product is needed urgently and cannot delay release With regulatory justification and robust real-time oversight But for a validation batch — unless urgency or rarity justifies it — this is not the preferred approach. As a QP, I would: Expect validation protocol and acceptance criteria pre-approved. Ensure the process is defined, controlled, and monitored per Annex 15. Review data from the pilot/scale-up batches before approving commercial process validation. Only consider concurrent validation if justified by risk and regulatory alignment.

Question 48

Scenario 13 follow up: When would you consider doing con current validation?

Answer 48

When consider: There is limited historical data (e.g. rare disease, low-volume product) Product is needed urgently and cannot delay release With regulatory justification and robust real-time oversight But for a validation batch — unless urgency or rarity justifies it — this is not the preferred approach.

Question 49

Was there any difference if the API was sourced from US comparing to India?

Answer 49

White list countries: I JUS BACK US is white list country, but India is not. This mean when API batch importing from non-white list country to UK/EU, require Written Conformation from India Authority.

Question 50

Where the reference samples/retained samples would be kept (API+FP)?

Answer 50

EU GMP annex 16, 19 and 21 - 1. For Finished Products Manufactured in the UK or EEA - Reference sample: → Stored at the site performing QC testing, ideally in the UK. - Retention sample: → Stored at the site of QP certification (UK releasing site). 2. For Products Imported from an MRA Country (e.g. Switzerland, Australia) (Annex 19, Section 7.2.1) - Reference sample: → May be retained at the MRA manufacturing site, if: Covered by a written agreement between the importer/QP and manufacturer. QP has timely access to the sample if required. - Retention sample: → Must be kept within the UK/EEA, preferably at the site of QP certification. Additional Note: If reference samples are stored outside the EEA, separate retention samples must be kept within the EEA (Annex 19, section 8.2). 3. For Products Imported from a Third Country (non-MRA) (Annex 19, Section 7.2.2 and Annex 21) Importation testing is required, so: - Reference sample: → Must be stored at the site performing QC testing (UK importation testing site). - Retention sample: → Must be stored within the UK, preferably at the site of QP certification. 4. For API (Active Pharmaceutical Ingredient) Reference Samples (Annex 19, Section 7.2.3) - Reference samples of starting materials and packaging materials (e.g. APIs): → Should be kept at the original site where they were used in the manufacture of the product. That means: If the API was used in the EEA: the EEA site holds the API sample. If outside EEA: the third-country site where the API was used retains the sample.

Question 51

What would you consider as a QP importing IMP to the UK?

Question 52

Please talk about the IMP QP oversight - what need to check?

Question 53

Scenario 14: You are a QP at an MIA site in the UK overseeing the certification of commercial batches of Oral Solid Dose. API - Australia DP & PKG - Australia. The finished product is being imported to the UK for certification, however site of importation is to your third party entity (i.e., not being imported directly to my MIA premises, instead to a storage and distribution facility). What would you expect to see to enable you to certify this product?

Answer 53

- What exactly was the product, is it a controlled drug etc, - Annex 16 delegable duties expanded on here - WDA(H) requirements for the storage site - Named as storage site on my MIA, product stated in Annex 8 etc - Discussed MRA’s again for Australia and (Approved Country for Batch testing)

Question 54

Scenario 14 follow up: Same product as above, however the supply chain has now changed to the following: API - China Bulk tablet - UK Primary PKG - USA Secondary PKG - Republic of Ireland (and cert for EU Market) Physical Importation & QP Certification - UK What would you expect to see in the following supply chain?

Answer 54

They were rushing me along in this supply chain, my usual approach is to give in great detail the requirements for each site in the chain, they wanted the key differences from the earlier supply chain.

Question 55

Scenario 15: You work as a QP, manufacturing site changes from UK to Turkey, API site changes from EU to China.

Answer 55

-MIA QP perspective -MA QP perspective Talk through the method transfer process  in depth conversation (impurities, method transfer, API registration, validations, key documents, licence variation etc.)

Question 56

Batch specific variation vs unexpected variation discussion - explain the difference?

Answer 56

A batch-specific variation is typically a contained, understood variation within a single batch — it may still meet specification and be attributable to a known cause. In contrast, an unexpected variation is a departure from expected process or product behaviour, which could indicate a loss of control or an emerging trend — and as a QP, this would prompt a more comprehensive investigation, possibly escalating into trend review or even recall assessment depending on severity.

Question 57

Difference in IMP QP oversite and IMP QP declaration?

Answer 57

IMP QP over site - IMP product certified by EU QP. IMP QP declaration - QP declaration for IMP product imported from non-approved country, ensuring the IMP has manufactured and tested under equivalent EU GMP condition.

Question 58

What is the SMF , where will you find the guidance, what are the contents in it. Discuss a lot about QMS requirement in the SMF, the licenses reference

Answer 58

“The Site Master File (SMF) is a regulated, high-level summary document prepared by the manufacturer to describe the GMP-related activities carried out at a pharmaceutical manufacturing site, including manufacture, packaging, testing, storage, and release. It is submitted to regulatory authorities during licensing or inspections and provides a concise overview of the site’s quality management system, facilities, personnel, equipment, processes, and compliance history. The SMF must be accurate, up to date, and part of the site’s QMS (Annex 15 and Volume 4 Part III guidance). It should not exceed 25–30 pages excluding appendices.” Reference: The format and content are defined in: EU GMP Volume 4, Part III – “Explanatory Notes on the Preparation of a Site Master File” (SANCO/C8/AM/sl/ares(2010)1064603) Key Sections of the SMF (as per EU GMP Part III): 1. General Information Site name, address, GPS/DUNS code, contact info Valid manufacturing authorisation (Appendix 1) List of dosage forms (Appendix 2), GMP certificate (Appendix 3) Summary of authorised activities (e.g. MIA/IMP scope) 2. Quality Management System Overview of the QMS (e.g. ISO-based, ICH Q10 principles) QMS elements: deviation handling, change control, CAPA, QRM, OOS/OOT Product Quality Review (PQR) approach Role and qualification of the QP / Authorised Person Details of supplier qualification and falsified medicine prevention Use of external labs, scientific advice (Appendix 4) 3. Personnel Organisational chart (Appendix 5) Number and roles of staff in QA, production, QC, and distribution QP responsibilities for batch certification and product release 4. Premises and Equipment Layout of site, flow charts (Appendix 6) Cleanroom classifications and HVAC description Water systems (WFI, PW) with schematics (Appendix 7) Other utilities (compressed air, nitrogen, steam) List of critical equipment (Appendix 8) 5. Documentation System Overview of document control (paper vs. electronic) Off-site archive arrangements, retrieval time, data integrity measures 6. Production Activities Types of products manufactured (incl. IMPs) Validation strategy (prospective, ongoing) Policy on rework, reprocessing Material handling, quarantine, and storage systems 7. Quality Control Description of physical, chemical, microbiological, and biological testing Reference to outsourced testing (if applicable) 8. Distribution, Complaints, Product Defects & Recalls Overview of distribution routes (EU, non-EU) Environmental control during transport (e.g. temperature) Recall system and complaint handling procedures 9. Self-Inspection System Frequency, scope, and follow-up of internal audits Important Appendices: Appendix 1 – MIA/IMP authorisation copy Appendix 2 – Product list Appendix 3 – GMP certificate Appendix 4 – List of outsourced labs/CMOs Appendix 5 – Organisation charts Appendix 6 – Site layouts and material/personnel flow Appendix 7 – Water system schematics Appendix 8 – Critical equipment list

Question 59

How could you ensure that the API PQR data is correct?

Answer 59

- QTA cover the aspect of accurate PQR - check External audit report - Periodical supplier review and audit - Comparison our PQR in API quality

Question 60

What do you need for an effective PQS and how would you set one up?

Answer 60

- use reference ICH Q9, Q10 and EU GMP chapter 1 - secure visible support from senior management to make sure enough resource for QMS management - define Quality Policy and objectives - Documented SOP with proper document control - set KPI for QMS for monitor performance - monitor trending data in regular meetings - periodical self-inspection; external audit and CAPAs - Use PQR

Question 61

What is a PQR and the contents?

Answer 61

reference - EU GMP chapter 1 Review of: 1. failed batch 2. QC tests results; ICPs results 3. Major deviations and investigations, CAPA effectiveness 4. CCs for mfg/testing process 5. CAPAs since last PQR and effectiveness check 6. Quality of staring material supplier including packaging 7. QTAs 8. Qualification status of relevant equipment, Utilities such as Hvac, water system 9. MA variations 10 Recall, complaints 11. on-going Stability programme 12. Validation status

Question 62

Your company are looking at acquiring a new (existing) manufacturing site. What would you assess as a QP?

Answer 62

1. CC open and due diligence 2 Impact on MA - variation (type2? need clarification with Regulatory Affairs) 3. Impact on licence: new site holds appropriate MFG licence to cover the activities, importation 4. Impact on GMP: - GMP certification, - Audit report - QP declaration (new mfg site) - Supplier Map update - importation testing arrangement if non-MRA country. - QTA in place - PQR access arrangement - Technology; analytical method transfer: Traditional validation - On-going stability programme - put first batch

Question 63

Cp and Cpk for an attribute in the PRA are 1.66 and 0.6 respectively. What does this tell you about the process?

Answer 63

“Cp and Cpk are process capability indices used to evaluate how well a process is performing relative to its specification limits. Cp (Process Capability Index) measures the potential capability of the process — i.e. how wide the process spread is, assuming it’s centred between the upper and lower specification limits. Cpk (Process Capability Index – adjusted for centering) measures the actual capability — taking into account how far the process mean is from the centre of the specification limits. In this case: Cp = 1.66 → suggests the process variation is acceptable (tight distribution), and the process could be capable if centred. Cpk = 0.6 → shows the process mean is off-centre, and parts of the output are likely outside the specification limits. The low Cpk indicates that the process is not currently capable of consistently producing product within specification. The system is not robust enough, as a robust process typically requires both Cp and Cpk to be ≥ 1.33 (with ≥ 1.67 preferred in critical GMP environments). As a QP, I would raise this concern in the PQR and expect a CAPA or investigation to address the shift in process centring and determine if it poses a quality risk.”

Question 64

What metrics from management review would increase your confidence in acting as a certifying QP at this site?

Answer 64

Review of - failed batches - Major Deviation, Investigation, CAPA effectiveness - CC related in manufacturing and testing and CC effectiveness - starting material suppliers quality - Recall/customer complaints - QTAs - Qualification status of equipments, utilities like HVAC/Water system - MA variation change - On-going stability study and negative trend - Post marketing commitments, licence variations - CAPAs from last PQR and its effectiveness - QC tests and IPCs results

Question 65

What types of validation are there?

Answer 65

- Traditional (prospective) - Concurrent (limited occasion) - Continuous (continues manufacturing, QBD) - retrospective (no longer acceptable)

Question 66

Talk through a cleaning validation process?

Answer 66

1. Risk-Based Approach and HBEL Integration Cleaning validation must be risk-based and scientifically justified. A Health-Based Exposure Limit (HBEL) must be established for each product by a qualified, experienced toxicologist — as required by PIC/S Q&A #4 and MHRA. This is the foundation for cross-contamination control, not just for setting cleaning limits, but also for assessing organisational and technical controls. Use the HBEL to determine the Maximum Allowable Carryover (MACO), considering worst-case equipment/product interfaces and unit dose exposure. The HBEL must drive the QRM process, not the other way around. 2. Equipment Mapping & Risk Assessment Prepare an equipment train map, identifying shared equipment and flow paths. Perform a cross-functional risk assessment involving Production, Engineering, QA, and QC. Identify hard-to-clean parts, dismantling requirements, retention points, hold times, and campaign lengths. Look at contamination risk at both batch and unit dose levels, using real drawings and floor plans (per MHRA blog). Visual thresholds must be studied — don’t assume visual inspection alone is sufficient. 3. Cleaning Method Development Select appropriate cleaning methods: manual, automated, or combination. Perform cleanability assessments: solubility, potency, formulation type. Define sampling strategy: Swabbing for small or hard-to-clean areas. Rinse for large surface areas or closed systems. Validate analytical methods (LOD, LOQ) and prove recovery rates ≥70% on representative surfaces. Perform visual residue limit (VRL) studies if visual inspection is proposed as a verification tool post-validation — and apply a margin of safety for variable lighting/conditions. 4. Cleaning Validation Protocol Protocol must be approved prior to execution and include: Acceptance criteria based on PDE/MACO Sampling and analytical methods Number of runs (more than 3 may be needed to account for variability in manual cleaning) Hold time studies Campaign limits Training and competency assessment for cleaning operators 5. Execution and Verification Document all cleaning steps and sampling with traceability. Investigate any OOS results or failures via deviation process — include re-training and root cause analysis. Verify success of cleaning using analytical methods, not just visual inspection. Sole reliance on visual inspection is only acceptable if supported by a VRL study and HBEL margin of safety, as described in PIC/S Q&A #7. 6. Post-Validation Control Strategy After validation: Define ongoing verification strategy (e.g. periodic swab/rinse testing, especially for high-risk products or manual cleaning). Continue using analytical testing at product changeover unless a robust risk-based justification is in place. Cleaning validation is not a one-time activity — revalidation is triggered by: New product introduction Change in cleaning method, equipment, or cleaning agent Facility layout change Adverse trends in cleaning failures 7. Integration into PQS Cleaning validation and cross-contamination control must be part of the site’s QMS and Quality Risk Management programme (ICH Q9). The QRM process must: Document organisational and technical controls Avoid over-reliance on paper procedures — observe real practices during validation and inspection Be periodically reviewed in line with process and product risk

Question 67

You are now going to move your existing production onto the new site. What are your concerns?

Answer 67

1. cc open 2. Supply chain map update - make sure if the new production site in teh UK/EU/MRA/Non-MRA country 3. Impact on MA - variation 4 Impact on Licence -new site hold appropriate licence 5. GMP cert or equivalent 5.1. Audit and QP declaration for new mfg site 6. Product impact: val

Question 68

What is a Site Master File? What are its contents?

Answer 68

Model Answer: A summary of GMP activities at a site. Key sections include PQS overview, production operations, QC, premises, personnel, and self-inspection. Tips: List all 6 chapters concisely. Don’t overtalk. Use structure: Chapter 1 – PQS, Chapter 2 – Personnel, et

Question 69

What is a QP Declaration and when is it required?

Answer 69

Model Answer: A QP Declaration confirms the API is manufactured under GMP. Required for all API manufacturing sites, including EU and third countries. Needed when submitting MA variations. Tips: Differentiate from written confirmation (third countries only); QP Declaration is always needed.

Question 70

Scenario 16: API from Singapore, manufacturing/testing in France, packaging in Turkey, QP cert in UK – what do you need to ensure as QP?

Answer 70

Model Answer: Have a supply chain map. Check authorisations for all sites. Written confirmation for Singapore. Full retesting in UK due to Turkey being a third country. Review batch records, ensure QTA in place, consider stability data and Annex 16 sampling. Tips: Bring in Annex 16 & 21. Reference & retention sample handling. Justify UK testing.

Question 71

Scenario 16 follow up: Singapore API site licence revoked. You’re the sole supplier. What do you do?

Answer 71

Model Answer: Start with concerns for GMP, MA, and patient safety. Do impact assessment, root cause, change control. Inform DHSC and EMA (via EMSP). Consider alternate supplier, assess impurity profile, initiate tech transfer and validation. Tips: Always start with “My concern is patient safety.” Mention regulatory contact and cross-functional team input.

Question 72

Scenario 16 follow up: What documents support QP certification for a batch?

Answer 72

Model Answer: * Certificate of Analysis (CoA) * Certificate of Conformity (CoC) * Manufacturing and packaging records * Deviation and OOS investigations completed before certification * Validation status of process and equipment * Control report (for veterinary) * Any Official Control Authority Batch Release (OCABR) if applicable Tips: * Structure your answer as a checklist to demonstrate systematic thinking. * Emphasise traceability and completeness.

Question 73

Scenario 16 follow up: What’s the difference between a PQR and ongoing method validation?

Answer 73

Model Answer: A PQR (Product Quality Review) is a periodic (usually annual) summary of product performance, including deviations, OOS, complaints, yield, and trends. Ongoing method validation (or continued method verification) ensures that analytical methods remain suitable through periodic review of system suitability, accuracy, precision, and robustness based on accumulated data. Tips: * PQR is product-focused; ongoing method validation is method-specific. * Both may use statistical tools like Shewhart charts, control limits, Cpk/Ppk.

Question 74

Scenario 16 follow up: What is ongoing process verification (OPV), and how does it differ from a PQR?

Answer 74

Model Answer: OPV is the real-time or continuous monitoring of process parameters to ensure control during routine production. PQR is a retrospective review. OPV may detect issues faster but may have limited historical context (e.g., rolling 100-batch trend). PQR can detect longer-term trends missed by OPV. Tips: * Mention ICH Q8 and Annex 15 for OPV. * Highlight statistical tools: control charts, trend analysis, Cpk/Ppk, regression analysis.

Question 75

Scenario 16 follow up: You notice a downward trend in assay across 1,000 batches during a PQR that wasn’t picked up in rolling 100-batch CPV. What do you do?

Answer 75

Model Answer: I would: *Investigate potential root causes (e.g., raw material change, equipment drift). *Assess the stability data to predict if product might go out of spec during shelf-life. *Perform regression analysis on assay data. *If extrapolated data shows OOS before expiry, initiate a recall (likely Class 2). *If stable and justified, continue monitoring with a CAPA plan. Tips: *Differentiate between out-of-trend (OOT) vs out-of-spec (OOS). *Reference EMA’s Q&A on trend detection.

Question 76

Scenario 17: There was a big supply chain question – dry powder oral suspension, API from India, Bulk in Germany, Packaged/Tested/QP cert in GB for NI (about 20 minutes).

Question 77

Scinario 17: You are a new QP of a large generic manufacturer company. You came to know that the ongoing stability programme is not up to date with most of the products? Your concerns as a QP? How will you manage the situation? (About 25 minutes)

Question 78

r. You have a lot of batches on market and how will you manage this, you do not have staff to perform all testing.

Question 79

s. Yes, you can transfer it to another registered laboratory listed on the MA. What will you require to see? How do you know transfer was successful?

Question 80

t. All transfers have been carried out 3 years ago and no testing since then, are you concerned?

Question 81

u. How will you prioritise what you need to test, there are 60 odd products?

Question 82

v. So now you have tested the annual stability of all the 15 products, all of them fail the test results at the current timepoint.

Question 83

w. How will you assess the data? What statistics you are going to use?

Question 84

x. What other data you will require to make assessment on your batches?

Question 85

y. How will you know which batches might be affected?

Question 86

z. What are you going to do with these batches? These are batches which you are only MA holder.

Question 87

aa. What options will you have to keep batches on market?

Question 88

ab. Are you going to let DMRC know all 15 products? Your director comes to you and says this will be a bad reputation to the Company. Are you going to hold few batches from notifying DMRC?

Question 89

ac. What level of recall and why?

Question 91

Scinario 18: You are a new QP of a large generic manufacturer company. You came to know that the ongoing stability programme is not up to date with most of the products? Your concerns as a QP? How will you manage the situation? (About 25 minutes)

Question 92

Follow up: r. You have a lot of batches on market and how will you manage this, you do not have staff to perform all testing.

Question 93

Follow up: s. Yes, you can transfer it to another registered laboratory listed on the MA. What will you require to see? How do you know transfer was successful?

Question 94

Follow up: t. All transfers have been carried out 3 years ago and no testing since then, are you concerned?

Question 95

Follow up: u. How will you prioritise what you need to test, there are 60 odd products?

Question 97

What should a PQR for an API contain?

Answer 97

A: A PQR for an Active Pharmaceutical Ingredient (API) should provide a comprehensive, periodic evaluation of its quality and manufacturing performance. As per EU GMP Part II (ICH Q7), it should include: • Batch data: Total number of batches manufactured and released, with yield and quality trends. • Deviations and investigations: Summary of deviations, non-conformances, OOS/OOT results. • Changes: Any changes implemented via change control procedures. • Reprocessing or reworking: Details of any batches that underwent reprocessing or reworking. • Stability data: Summary and evaluation of ongoing stability studies. • Impurity profile: Comparison of actual impurity levels with historical data and specifications. • Quality-related complaints and recalls: Any complaints received and actions taken. • Regulatory commitments: Updates on post-approval changes or variations, if applicable. • Supply chain: Review of critical materials, supplier qualification status, and QTA compliance. • Validation and equipment: Status of critical equipment qualification and process validation. • Recommendations: Summary of findings, including actions for improvement or CAPAs if needed.

Question 98

API from India, bulk manufacture in USA, finished product in France, shipped to UK (GB) and Northern Ireland.

Answer 98

• User structured the answer: • API: TA, QP declaration, written confirmation (EU/UK requirement). • USA (bulk): MIA, GMP certs, executed batch records, GDP compliance. • France (finished product): MIA, GMP certs, QC testing, partial batch certification (Annex 16 template). • UK (certification): Windsor Framework allows UK-wide licensing. • QP verifies PQS, batch records, transport data, stability, deviations, approved labels before certification. • Feedback: • User handled complex chain confidently, linking sites via GDP and regulatory documentation. • Additional tips: Reference Annex 16, Annex 19, guidelines on importation, emphasize reference/retention samples.

Question 99

As a QP, how would you use PQS KPIs and metrics to support your batch release decision-making process? Can you explain which specific KPIs you would focus on and how you differentiate between general PQS health metrics and those directly impacting batch certification?

Answer 99

⸻ Model Answer: As a QP, ensuring that the Product Quality System (PQS) is operating effectively is fundamental to my batch certification decision. While general PQS health is important, I focus specifically on KPIs and metrics that directly impact the batch under review to ensure patient safety and product quality. ⸻ Key KPIs/metrics directly impacting batch release: 1. Batch-specific deviations: • I review open and closed deviations related to the batch and assess if any critical or major deviations could impact product quality, safety, or compliance. • Ensuring CAPAs from deviations are effective and closed, or if still open, assessing the risk to the batch. 2. Change controls (impacting the batch): • Check for open or ongoing changes that could affect materials, equipment, process, or analytical methods linked to the batch. • Confirm that any relevant change controls have been fully assessed and implemented before release. 3. Complaints related to previous batches: • I review recent complaints or quality defects to identify any trend or recurring issue with the product that could impact the current batch. 4. Documentation readiness: • Ensure batch manufacturing records, QC data, and Certificates of Analysis (CoA) are complete, reviewed, and approved. • Confirm that traceability and data integrity requirements are met (e.g., ALCOA+ principles). ⸻ PQS Health Metrics (broader view): While general PQS metrics like CAPA trends, audit findings (internal/external), and supplier performance inform my confidence in the overall PQS, they serve as a background assessment rather than immediate batch-specific decision factors. For example: • If I observe a trend of recurring audit findings or long overdue CAPAs, this may prompt me to heighten scrutiny over specific areas (e.g., documentation, training, EM). • However, unless these directly impact the current batch or associated systems, they would not in themselves prevent batch release but might require escalation to senior management. ⸻ Summary: In my role as QP, I differentiate between: • Batch-specific KPIs (directly impacting release): Deviations, change controls, complaints, documentation readiness. • General PQS health metrics (systemic performance): CAPA trends, audit follow-ups, supplier metrics. Ultimately, batch release is a risk-based decision, and I ensure real-time PQS data supports informed certification, safeguarding patient safety and compliance.