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© Crown copyright 2008

Safeguarding public health

Examples of QP Issues

Di MorrisGMP Inspector11 November 2008

November 2008Di Morris




ACTIVE PHARMACEUTICAL INGREDIENTS

• Company X had not audited API site:

They purchased audit package

- It was a re-audit to check status

- Incomplete actions found – some critical

QP approved package

MHRA reviewed

- Resulted in triggered API inspection

- Critical deficiencies found

Status ongoing





INVESTIGATIONAL MEDICINAL PRODUCTS

• Batch Certification issues

• QP does not have access to or not even involved with:

Stability data/reports

The CTA application and IMPD dossier

Substantial amendments such as expiry extensions

Product Specification Files

• So how can a batch be certified?





THIRD COUNTRY IMPORTS

• Batch Certification and Release issues

Samples not representative of the bulk shipment method.

Batches released before batch arrives on site.

Batch release SOP not aligned to Annex 16.

Manufacturing site not audited.

EU GMP compliance statements not provided.

QPs not aware of the TSE requirements.

QPs do not see batch / product specific deviations or changes.





THIRD COUNTRY IMPORTS • Batch Certification and Release issues continued

Stability data and reports not seen/reviewed.PQR reports not seen/reviewed.- Analytical data on import not compared with third country

dataTechnical Agreements do not specify in particular:- OOS data and investigations to be provided.- Complaint investigations that may affect the products they

release.





THIRD COUNTRY IMPORTS • Batch Certification and Release issues continued

QPs not aware of API requirements.- There was no documented system in place to ensure that all

suppliers of APIs were demonstrated to be operating in compliance with EU GMP

Recall systems do not involve the certifying QP.Product shipped under Quarantine:- No procedure in place- No communication to the certifying QP to prevent release.MRA situations:Batches imported from Switzerland without QP involvement.





THIRD COUNTRY IMPORTS • Batch Certification and Release issues continued:

QPs not aware of product related non conformances such as Failure to perform re-qualificationsDatalogger deficiencies:- Not calibrated.- Set points outside product limits.- Data not reviewed prior to batch release.- Excursions not investigated.





TECHNICAL AGREEMENTS

• These are the basic requirement for ensuring compliance with regard to: - Manufacturing Authorisation.- Marketing Authorisation.- Responsibilities of Contract Givers and Contract Acceptors.






• They are essential given complexity of - Manufacturing operations – 2 or more sites often involved

including overseas sites- Contract manufacture- Contract Analysis- Regulatory activities- Complaints- Pharmacovigilance





TECHNICAL AGREEMENTS (TAs)

• Technical Agreement (TA) deficiencies found:- No TA defining responsibilities between the company and their

affiliates.- No TA defining responsibilities between the contract giver and

contract acceptor – i.e. TAs not written.- No TAs in place between the company and the QPs named on

the MIA.- The TA with the contract manufacturer stated that they were

responsible for release to the market, contrary to the information in the Marketing Authorisation.

- No TA SOP defining the GMP requirements.






• Technical Agreement (TA) deficiencies found:

- The TA was not available at the time of inspection.

- The TA was not approved.

- The TA did not require notifying the Contract giver of any changes to

the subcontracted analysis provider.

- The TA did not state who was responsible for recalls and complaints.

- There was no detail as to how deviations raised during routine

manufacture would be communicated to the client.

- There was no reference to the specifications, analytical methods and

or the acceptance criteria.






• Technical Agreement (TA) deficiencies found:- There was no indication as to whose responsibility it was to

ensure materials and testing were updated in line with pharmacopoeia changes.

- No mention of reference and retained samples- The TA lacked detail as to the responsibilities for Product

Quality Review.- The TA lacked detail as to the responsibilities for stability

monitoring.






• Contract QP Agreements – they do not detail:

The frequency of attending the site.

The time spent on site.

The duties to be performed.

How they will be kept current – with site issues and training.

To be on site during regulatory Inspections.





GENERAL BATCH CERTIFICATION AND RELEASE ISSUES• Batch Release procedures are written without:

QP Involvement.Reference to Annex 16.

• QPs are not involved with Quality System requirements:Not involved with self inspections.Not involved with complaints.Do not see all pertinent deviations or accept poor investigations.Not involved with PQRs.The QP has continued to certify batches despite a number of key elements of the quality system not being in place.





GENERAL BATCH CERTIFICATION AND RELEASE ISSUES

• QPs do not see the Marketing Authorisations:

Do not know if manufacturing process complies with the MA.

Do not know what the stability commitments are.

Do not know if the analytical methods used are in the MA.

Do not know what contract laboratories are in the MA.

Cannot assess the impact of any site changes.

Do not receive other European approvals of variations.

They are unaware of any Post Marketing commitments





GENERAL BATCH CERTIFICATION AND RELEASE ISSUES• Marketing Authorisations:

The Change Control SOP did not address requirements for

regulatory review and approval by the QP.

QPs not involved in licence variations.

Batch Record SOP did not describe how these documents

were checked for compliance with relevant details in the

Marketing Authorisations.

No Technical Agreement in place between the site and off-site

Regulatory Affairs dept. to ensure QPs and other pertinent staff

are involved.





GENERAL BATCH CERTIFICATION AND RELEASE ISSUES• The Myth of QP discretion• There isn’t any myth – QPs do not have discretion to release

batches with attributes outside their limits. • If the attribute is registered and it is found to be outside of the

limits then a batch specific variation is needed. A full justification for release is required from the QP.

Deficiencies found:- QPs releasing product with reduced shelf lives.- QPs releasing product not compliant with the product

specification.- QPs releasing product not matching the Marketing

Authorisation.





GENERAL BATCH CERTIFICATION AND RELEASE ISSUES• Contracted out audits of facilities:

Suitability of the auditor.Audit scope is not known.Product specific areas not covered / Areas audited not known.Time taken is too short.Acceptance of scant reports.Audit observations not followed through.

• The Agency will be checking the information supporting a QPs compliance approval of API and overseas sites.





POST INSPECTION COMMITMENTS

An increase in the number of instances where timetable for completion not complied with.The inspector has not been informed.In a number of cases, either a significant delay (right up to next inspection) or not even completed.Very serious issue & could have implications for licence/certificates and the QPs certifying products.Trust is significant part of post-inspection process.Delay in implementation should be exceptional and the QPs should know.If delay likely, contact your inspector, don’t leave it!





MHRA Web Page

Serious Issues:

There are 40 deficiency Classifications the analysis of the data from Post Inspection Letters will be published on the MHRA website.

It is proposed that the following will be reported:- Number of Inspections (total): - Number of Critical deficiencies- Number of Major deficiencies- Number of Serious issues per inspection- Top 5 serious issues





MHRA Web Page

Serious Issues:

For 2007/08

- Number of relevant Inspections (total): 598- Number of Critical deficiencies reported: 28- Number of Major deficiencies reported: 838

- Data reviewed to date indicates the top 5 deficiencies:- Investigation of Anomalies- Documentation (QMS, Procedures)- Quality Management- Supplier Audit and technical agreements- Change Control/Management





Serious Issues 2007/08

Total Deficiency per Quarter

0255075

100125150175200225250275300325350375400425450475500525550575600625650

Q1 2007-08 Q2 2007-08 Q3 2007-08 Q4 2007-08

Quarter and Year

No o

f Def

ects

Defect 1 Defect 2

Defect 3 Defect 4

Defect 5 Defect 6

Defect 7 Defect 8

Defect 9 Defect 10

Defect 11 Defect 12

Defect 13 Defect 14

Defect 15 Defect 16

Defect 17 Defect 18

Defect 19 Defect 20

Defect 21 Defect 22

Defect 23 Defect 24

Defect 25 Defect 26

Defect 27 Defect 28

Defect 29 Defect 30

Defect 31 Defect 32

Defect 33 Defect 34

Defect 35 Defect 36

Defect 37 Defect 38

Defect 39 Defect 40





Crown copyright 2008

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Good Manufacturing Practice (GMP) Symposium

Best practice guidance for Qualified Persons

11 November 2008

Medicines and Healthcare products Regulatory Agency

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