| slide 1 of 18 26 november 2009 prequalification: inspection activities prequalification programme:...
Post on 13-Dec-2015
237 Views
Preview:
TRANSCRIPT
| Slide 1 of 18 26 November 2009
Prequalification: Inspection Activities
Prequalification Programme: Priority Essential Medicines
Prequalification Programme: Priority Essential Medicines
WHO Prequalification of Generic Medicines approved by Stringent Regulatory Authorities
Presented by
Mr. Deus K Mubangizi
Technical Officer
mubangizid@who.int
Organization of prequalification inspections and applied standards
| Slide 2 of 18 26 November 2009
Prequalification: Inspection Activities
In this presentation:In this presentation:
Inspection activities wrt WHO-PQ Mission, Strategy and Process
Scope of inspection activities: FPPs, APIs, BE/CROs, QCLs
Norms and standards used
Risk-based approach to inspections
Use of inspection reports from other NMRAs
Inspection frequency, duration and scheduling
Inspection process
Classification of deficiencies
Conclusions following an inspection:– Acceptable level of compliance– Conclusion on level of compliance awaits CAPAs– Unacceptable level of compliance
Results and transparency: WHOPIRs and NOCs on website
| Slide 3 of 18 26 November 2009
Prequalification: Inspection Activities
Inspection Activities and scope wrt PQ Mission & Strategy
Inspection Activities and scope wrt PQ Mission & Strategy
Prequalification Programme aims to make quality priority medicines available for the benefit of those in need through:
– Evaluation of a dossier of product quality, safety and efficacy information
– inspection of• manufacturing sites for FPPs and APIs,• BE studies/CROs,• QCL (National or independent)
– building national capacity for sustainable manufacturing and monitoring of quality medicines.
| Slide 4 of 18 26 November 2009
Prequalification: Inspection Activities
USPBP
Ph. Eur.Ph. Int.
Prequalification Programme: International norms, standards and guidelines used in inspection activitiesPrequalification Programme: International norms, standards and guidelines used in inspection activities
Other guidelines e.g. ICH, ISO
min0 1 2 3 4 5 6
Norm.
0
50
100
150
200
DAD1 A, Sig=270,4 Ref=360,100 (D:\2\AMR_EA\29070415.D)
1.7
28 -
Ison
iazi
d
5.4
78 -
Eth
ambu
tol H
Cl
| Slide 5 of 18 26 November 2009
Prequalification: Inspection Activities
Risk based approach to inspections Ref: SOP 401.1: Inspection Frequency and Scheduling
Risk based approach to inspections Ref: SOP 401.1: Inspection Frequency and Scheduling
Inspections are scheduled on a risk basis, taking into account all known factors that could affect quality, safety and efficacy, including the following:– results of previous WHO inspections results of inspections by other National Regulators– type of APIs, products and dosage form manufactured or -
activities performed recalls or complaints since last inspection results of product testing – significant changes within the manufacturer, e.g. changes to
key personnel, buildings, equipment, products etc.– any other relevant information (e.g. variations)
| Slide 6 of 18 26 November 2009
Prequalification: Inspection Activities
Prequalification Programme: Use of Inspection reports from other NMRAsPrequalification Programme: Use of
Inspection reports from other NMRAs An inspection by the PQP may be omitted when other acceptable evidence of
GMP compliance is provided by the FPP or API manufacturer.
An inspection by another acceptable organization, such as a PIC/S member country, or the US FDA, may be considered in lieu of a PQP inspection when:
– The inspection was conducted within the last 2 years, and The scope of the inspection covered the specific FPP or API in question, and The FPP or API manufacturer submits a copy of the last inspection report for
review by the PQP. (During the review, the inspectors will determine whether the inspection was comprehensive, covered the relevant areas appropriate to the product in question and that the inspection report supports the final outcome in accordance with WHO GMP).
– Irrespective of the above, the PQP reserves the right to inspect any FPP or API manufacturer if considered necessary.
Whether inspected by the PQP or GMP compliance is based on an inspection by another acceptable organization, on-going GMP compliance will be confirmed by WHO.
| Slide 7 of 18 26 November 2009
Prequalification: Inspection Activities
Guide to Manufacturer Risk ClassificationRef: SOP 401.1: Inspection Frequency and Scheduling
Guide to Manufacturer Risk ClassificationRef: SOP 401.1: Inspection Frequency and Scheduling
PRODUCT TYPE / ACTIVITY
RELATIVE RISK CATEGORY
CRITICALHIGHMEDIUMLOW
Finished Products:Sterile finished products
Non-sterile finished products
APIs:
Sterile APIs
Non-sterile APIs where there is a special risk (e.g. isomerism, polymorphism, special risk of harmful impurities, etc)
Other non-sterile APIs
QC Laboratories
CROs
| Slide 8 of 18 26 November 2009
Prequalification: Inspection Activities
RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION PROGRAMME
(1 of 2)
RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION PROGRAMME
(1 of 2)
API
Manufacturer
Present in Product(Ref. Nos.)
Number of Products
ParameterRisk = 2Risk = 1Risk Score
1PolymorphismYN
2Solubility in waterLowHigh
3SynthesisComplexNot complex
4SolventsHigh RiskLow risk
5ImpuritiesHigh RiskLow risk
6SterileYN
7FermentationYN
| Slide 9 of 18 26 November 2009
Prequalification: Inspection Activities
RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION PROGRAMME
(2 of 2)
RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION PROGRAMME
(2 of 2)
ParameterRisk = 2Risk = 1Risk Score
8ToxicityHighLow
9Activity/potencyHigh RiskLow risk
10Particle sizeHigh RiskLow risk
11Other property consideration
12Site compliance information (WHO/EDQM/Other)
NegativePositive
Total Risk Score
General remarks:
Last inspection dateOutcomeCompliant
Not Compliant
Inspection prioritization
High
Medium
Low
| Slide 10 of 18 26 November 2009
Prequalification: Inspection Activities
Guide To Inspection Frequency (in months)Ref: SOP 401.1: Inspection Frequency and Scheduling
Guide To Inspection Frequency (in months)Ref: SOP 401.1: Inspection Frequency and Scheduling
RISKCATEGORY
:
GMP Compliance Rating:
Acceptable:
UnacceptableGoodSatisfactoryBasic
Critical241812Determine on a case by
case basis
High302015Determine on a case by
case basis
Medium362418Determine on a case by
case basis
Low483624Determine on a case by
case basis
| Slide 11 of 18 26 November 2009
Prequalification: Inspection Activities
Inspection Duration Guide (on-site days)Ref: SOP 401.1: Inspection Frequency and Scheduling
Inspection Duration Guide (on-site days)Ref: SOP 401.1: Inspection Frequency and Scheduling
Manufacturer Size
RISK
CHMLCHML
Initial InspectionRe-inspection
Large54334332
Major44333322
Standard43323222
| Slide 12 of 18 26 November 2009
Prequalification: Inspection Activities
Inspection SchedulingInspection Scheduling
Initial inspections: are scheduled at a suitable time to avoid delaying product prequalification (max 180 days after dossier accepted).
Routine re-inspections: are scheduled so that the inspection is conducted within the period 3 months before and 3 months after, the due date.
– The due date for re-inspection is determined immediately after each inspection based on manufacturer risk classification and GMP compliance rating.
– Maximum validity of compliance status – 3 years
Special inspections: (e.g. to investigate a complaint or reasons for product failure) may be conducted at any time.
Follow-up inspections: (to close out deficiencies from the last inspection) may be conducted if deemed necessary.
– If a special or follow-up inspection is conducted, the timing of the next routine re-inspection is re-determined on a case by case basis.
| Slide 13 of 18 26 November 2009
Prequalification: Inspection Activities
Prequalification: Inspection ProcessesPrequalification: Inspection Processes
By a team of qualified and experienced inspectorsWHO representative (qualified inspector)
Inspector from well-established inspectorate (Pharmaceutical Inspection Cooperation Scheme countries – PIC/S)
National inspector/s invited to be part of the team but have NO decision making power (different GMP standards, potential conflict of interest)
Observer from recipient/developing countries (nominated by DRA of the country)
Scope: Compliance with guidelines: GMP, GCP, GLPData verification – data manipulation, falsification, (validation,
stability, clinical, bioanalytical) Quality control (QC, BAL, NQCL, IQCL)
| Slide 14 of 18 26 November 2009
Prequalification: Inspection Activities
Definition and classification of deficiencies Definition and classification of deficiencies
Deficiencies are descriptions of non-compliance with GMP requirements.
A distinction is made between deficiencies as a result of: -
– a defective system or,– failure to comply with the system.
Deficiencies may be classified as:– Critical Observation– Major Observation– Minor or Other Observation
| Slide 15 of 18 26 November 2009
Prequalification: Inspection Activities
Further considerations for classificationFurther considerations for classification
1. Classification of an observation is based on the assessed risk level and may vary depending on the nature of products manufactured, e.g. in some circumstances an example of an "other" deficiency may be categorized as "major".
2. A deficiency that was reported at a previous inspection and not corrected may be reported in a higher classification.
3. One-off minor lapses or less significant issues are usually not formally reported, but are brought to the attention of the manufacturer during the inspection.
| Slide 16 of 18 26 November 2009
Prequalification: Inspection Activities
Conclusion following an inspection:Conclusion following an inspection:
When there are "other" observations only:– considered to be operating at an acceptable level of compliance with WHO GxP.– The manufacturer is expected to provide CAPAs.– CAPAs are evaluation and followed up during the next routine inspection.
When the are "other" and a few "major" observations:– compliance with WHO GxP is made after the CAPAs have been assessed.– CAPAs for majors to include documented evidence of completion.– CAPAs paper evaluated ± an on-site follow up inspection.
When there are "critical" or several "major" observations:– considered to be operating at an unacceptable level of compliance with WHO
GMP, GCP, GLP guidelines.– Another inspection will be required
| Slide 17 of 18 26 November 2009
Prequalification: Inspection Activities
Prequalification Programme:Transparency - WHOPIRs and NOCs
Prequalification Programme:Transparency - WHOPIRs and NOCs
These are published in response to the WHA Resolution WHA57.14 of 22 May 2004, which requested WHO, among other actions:
– "3. (4) to ensure that the prequalification review process and the results of inspection and assessment reports of the listed products, aside from proprietary and confidential information, are made publicly available;"
A WHO Public Inspection Report (WHOPIR) reflects a positive outcome after an inspection
A Notice of Concern (NOC) is a letter reflecting areas of concern where the non-compliances require urgent attention and corrective action by the manufacturer or research organization.
| Slide 18 of 18 26 November 2009
Prequalification: Inspection Activities
ConclusionsConclusions
For PQP of generics approved by SRA, we shall largely rely on positive inspection outcome by SRAs - but reserve the right to inspect
Risk management principles are applied when:– scheduling inspections– conducting inspections– closing out inspections
Inspections are conducted according to written SOPs:– No bias or subjectivity – each deficiency is referenced to a guideline,
standard or norm.– No surprises in the report - Feedback is given every day and at the end
of the inspection.
Participation of NRAs in providing co-inspectors and observers is good for:
– Tapping into international skills– Ensuring transparency Facilitating ownership – possible faster national
penetration– Contributing to capacity building
top related