1. QUALITY OF PHARMACEUTICAL INGREDIENTS
WHO Prequalification Programme: Priority Essential Medicines
WHO GMP and API Inspections
Presented by
Mr. Deus K Mubangizi
Technical Officer

2. In this presentation: WHO-PQ: Inspection activities
WHO-PQ: Norms and standards
WHO-GMP for APIs versus ICH Q7A
Key elements of ICH Q7A
WHO-PQ API inspections: Observed trends and deficiencies
Conclusions

3. WHO Prequalification: Inspection activities
APIs,
FPPs
BE/CROs

4. Prequalification: Inspection Processes
By a team of qualified and experienced inspectors
WHO representative (qualified inspector)
Inspector from well-established inspectorate (Pharmaceutical Inspection Cooperation Scheme countries – PIC/S)
National inspector/s invited to be part and observe the inspection
Observer from recipient/developing countries (nominated by DRA of the country)
Scope:
Compliance with guidelines: GMP (ICHQ7), GCP, GLP
Data verification – data manipulation, falsification, (validation, stability, clinical, bioanalytical)
Quality control (QC, BAL, NQCL, IQCL)

5. RELATIVE RISK CATEGORY PRODUCT TYPE / ACTIVITY
Guide to Manufacturer Risk Classification Ref: SOP 401.1: Inspection Frequency and Scheduling
RELATIVE RISK CATEGORY
PRODUCT TYPE / ACTIVITY
LOW
MEDIUM
HIGH
CRITICAL
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

6. RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION PROGRAMME (1 of 2)
API
Manufacturer
Number of Products
Present in Product
(Ref. Nos.)
Risk Score
Risk = 1
Risk = 2
Parameter N Y
Polymorphism 1
High
Low
Solubility in water 2
Not complex
Complex
Synthesis 3
Low risk
High Risk
Solvents 4
Impurities 5
Sterile 6
Fermentation 7

7. RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN THE WHO PREQUALIFICATION PROGRAMME (2 of 2)
Risk Score
Risk = 1
Risk = 2
Parameter
Low
High
Toxicity 8
Low risk
High Risk
Activity/potency 9
Particle size 10
Other property consideration 11
Positive
Negative
Site compliance information (WHO/EDQM/USFDA/Other) 12
Total Risk Score
General remarks:
Compliant
Outcome
Last inspection date
Not Compliant
High
Inspection prioritization
Medium
Low

8. GMP Compliance Rating:
Guide To Inspection Frequency (in months) Ref: SOP 401.1: Inspection Frequency and Scheduling
GMP Compliance Rating:
RISK
CATEGORY:
Unacceptable
Acceptable:
Basic
Satisfactory
Good
Determine on a case by case basis 12 18 24
Critical (C) 15 20 30
High (H) 36
Medium (M) 48
Low (L)

9. Inspection Duration Guide (on-site days) Ref: SOP 401
Inspection Duration Guide (on-site days) Ref: SOP 401.1: Inspection Frequency and Scheduling
RISK
Manufacturer Size L M H C
Re-inspection
Initial Inspection 2 3 4 5
Large
Major
Standard

10. Risk-based approach in: 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 – potential risk harm to the user
Major Observation – major deviation from GMP
Minor or Other Observation – departure from good practice

11. Further considerations for classification
1. Classification of an observation is based on the assessed risk level and may vary depending on the nature of API 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.

12. Risk-based approach in: Conclusion following an inspection
When there are "other" observations only:
considered to be operating at an acceptable level of compliance with WHO GMP/ICHQ7.
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 GMP/ICHQ7 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/ICHQ7 guidelines.
Another inspection will be required

13. Transparency: Information put in public domain - 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.

14. Prequalification Programme: Use of Inspection reports from other NMRAs
An inspection by the PQP may be omitted when other acceptable evidence of GMP compliance (Report + CAPAs) is provided by the FPP or API manufacturer.
An inspection by another acceptable organization, such as a PIC/S member country, or US FDA or EU, 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 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 API manufacturer if considered necessary (specific product issues).
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 (also using update information from other NMRAs).

15. Prequalification Programme: International norms, standards and guidelines used in inspection activities to ensure wide applicability
Quality Assurance of pharmaceuticals. A compendium of guidelines and related materials. Vol.2, GMP and inspection. WHO, Geneva, 2007.
ICH Q7: GMP Guide for Active Pharmaceutical Ingredients, International Conference on Harmonization.
WHO GMP: water for pharmaceutical use. 39th Report. Geneva, WHO, 2005 (WHO TRS, No. 929), Annex 3.

16. Prequalification Programme: norms, standards and guidelines used…
WHO guidelines for sampling of pharmaceutical products and related materials. 39th Report. Geneva, WHO, 2005 (WHO TRS, No. 929), Annex 4.
Supplementary GMP guidelines for HVAC systems. 40th Report. Geneva, WHO, 2006 (WHO TRS, No. 937), Annex 2.
Supplementary GMP guidelines: validation. 40th Report. Geneva, WHO, 2006 (WHO TRS, No. 937), Annex 4.
Good Practices for National Pharmaceutical Control Laboratories. 36th Report. Geneva, WHO, 2002 (WHO TRS, No. 902), Annex 3.
USP BP
Ph. Eur.
Ph. Int.
Other guidelines e.g. ICH, ISO

17. Prequalification Programme: norms, standards and guidelines used…
WHO Expert Committee has revised WHO GMP for APIs at its meeting in October 2009 – adopted ICH Q7 principles.
Final editing going on but numbering of sections essentially similar to ICH Q7:
ICH Q7 is used in the discussions that follow.

18. WHO GMP and ICH Q7 II. QUALITY MANAGEMENT III. PERSONNEL
IV. BUILDINGS AND FACILITIES
V. PROCESS EQUIPMENT
VI. DOCUMENTATION AND RECORDS
VII. MATERIALS MANAGEMENT
VIII. PRODUCTION AND IN-PROCESS CONTROLS
IX. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES
X. STORAGE AND DISTRIBUTION
XI. LABORATORY CONTROLS
XII. VALIDATION
XIII. CHANGE CONTROL
XIV. REJECTION AND RE-USE OF MATERIALS
XV. COMPLAINTS AND RECALLS
XVI. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)
XVII. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS

19. WHO GMP for APIs / ICH Q7 Key definitions:
ICH Q7A
API starting material (API SM): a raw material, intermediate or an API used in the production of an API and incorporated as a significant structural fragment into the structure of the API. API SM can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API SM are normally of defined chemical properties and structure.
Intermediate: A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API.

20. ICH Q7A : Introduction
From what point does ICHQ7A start to be applied ?
“ICH Q7A applies from the point at which production of the API begins”.
Some indications are provided in Table 1 of ICH Q7A.
For synthetic process, this corresponds to the introduction of the API starting material into the process;
For other processes, on a case by case basis.

21. WHO GMP and Inspection of API manufacturers
Increasing GMP requirements

22. Main issue : How to define the API SM ?
World Health Organization
Main issue : How to define the API SM ?
6 April, 2017
RM (solvent, catalyst, reagent, filtration aid, decolorizing agent, chromatography phase, etc.)
C, H, O, N SM
(Intermediates)n
Active substance crude
Active substance (pure)
Only flow chart
GMPs do not apply
Detailed description
GMPs apply
API SM
Competent
Authorities
Industry
Photo : Internet

23. Application of ICHQ7
Companies should decide at which point ICH Q7A applies for their processes and should have documentation to support it. GMP applies from the declared and approved (API) SM in the registered file.
Stringency of GMP in API manufacturing increases from early steps to final steps
Advanced intermediates and crude APIs outsourced should be manufactured in compliance with GMP
This means that these “late intermediate and crude API” manufacturers should be considered as contract manufacturers (Q7A chapter 16 applicable).
Sterilisation and aspetic processing should be performed according to GMP related to Sterile pharmaceutical products.

24. World Health Organization
6 April, 2017
ICHQ7A: Scope
Q7A does not apply to :
vaccines, whole cells, whole blood and plasma
blood and plasma derivatives (plasma fractionation)
gene therapy APIs
bulk-packaged medicinal products
medical gases and manufacturing/control aspects specific to radiopharmaceuticals.
Q7A does not cover :
Safety aspects for the personnel engaged in the manufacture
and environmental issues.
vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation), and gene therapy APIs.
medical gases, bulk-packaged drug (medicinal) products, and manufacturing/control aspects specific to radiopharmaceuticals.

25. Review of some ICHQ7A’s concepts
Quality management (Chapter 2)
Responsibilities of the Quality Unit
Sections to
Tools for surveillance, monitoring and continuous improvement:
Internal audits/Self inspection (section 2.4)
Product Quality review (section 2.5)
Complaints, returns and recall (sections 14.5 and 15)
Change control (section 13)

26. Review of some ICHQ7A’s concepts
Change control
Raw materials, specifications, analytical methods, facilities, support systems, equipment (including computerized systems), processing steps, labelling and packaging materials
That can impact the quality of the API
Change control
Proposal drafted, reviewed and approved by the appropriate organisational unit
Change reviewed and approved by QU
Classification and impact assessment
Evaluation and monitoring + Notification

27. Review of some ICHQ7A’s concepts
Personnel (section 3)
Appropriate and regular GMP training periodically assessed (ICH 3.12)
Documentation (section 6)
Specifications for raw materials, intermediates, APIs, labelling and packaging materials (ICH 6.17)
Retention period specified for production, control and distribution records (ICH 6.13)
Contract manufacturers (section 16)
Contract manufacturers should comply with Annex 18 (ICH 16.10)
A contract or a formal agreement should exist between the contract acceptor and the contract giver (ICH 16.12).

28. Review of some ICHQ7A’s concepts
Facilities,equipment and utilities system
Facilities designed to prevent mix-ups and contamination
Precautions implemented based on a risk assessment
Equipment cleaning methodology and intervals appropriate to prevent build-up and carry-over of contaminants (degradants)
Critical operation with prolonged exposure to the environment
Non critical operation with prolonged exposure to the environment
Non critical or critical operation in a closed equipment

29. Review of some ICHQ7A’s concepts
HVAC systems (section 4.2)
Adequate ventilation, air filtration and exhaust systems should be provided where appropriate (ICH 4.21, 4.22)
Qualification and appropriate monitoring and operating range limits in place (ICH 4.20)
Water (section 4.3)
WHO potable water quality as a minimum (ICH 4.31)
Water for final isolation and purification steps for API for sterile products: test for microbial counts, objectionable counts and endotoxins.

30. Review of some ICHQ7A’s concepts
Material management (section 7.)
At least, identity testing of each batch on a sample representative of the batch (ICH 7.30)
Reduced testing for approved/validated suppliers (ICH 7.31)
Past quality history
Full analysis at least on three batches before starting reduced-testing
Reliability of the CoA checked at regular intervals
A documented supplier audit is not required but currently performed in the case of critical material by API manufacturers.
Precaution for bulk deliveries in non-dedicated tankers (ICH 7.22)

31. Review of some ICHQ7A’s concepts
Production (section 8)
Critical operations should be witnessed or subjected to an equivalent control (ICH 8.12)
Deviations should be documented, explained and/or investigated (ICH8.15)
Process time limits should be respected (ICH8.20)
Conditions and duration of storage of intermediates (ICH 8.21)
In-process sampling and controls (ICH 8.3)
approved written procedures, avoid risk of cross contamination during sampling, sample integrity

32. Review of some ICHQ7A’s concepts
Production
Blending operations (section 8.4)
Only batches meeting established specifications
Expiry or retest date of the blended batch based on the manufacturing date of the oldest batch included.
Should be controlled and documented – traceability
Validation for homogeneity following blending
OOS batches blended with others to meet specifications
1. Blending small batches to ↑se batch size
2. Blending tailings
APIs for OSDs/ Suspensions
1. Particle size distribution
2. Bulk density
3. Tap density

33. Review of some ICHQ7A’s concepts
Reprocessing or reworking for intermediates or APIs which do not conform to standards or specifications
Reprocessing (s. 14.2)
Repeating a step of the established manufacturing process
Crystallization, distillation, filtration, chromatography, milling, etc
Continuation to completes process after IPQC in not reprocessing
Introducing unreacted material into reaction is reprocessing
Included in the standard manufacturing process if reprocessing used for a majority batches
Reworking (section 14.3)
Reason for non conformance determined prior to any reworking
Involves a “treatment” different from the established one
Recrystallization with a a different solvent
Reworked batches to be subjected to appropriate evaluation, testing ± stability testing
Concurrent validation
Should have comparable impurity profile

34. Review of some ICHQ7A’s concepts
Recovery of Materials and solvents
Reactants, intermediates or APIs may be recovered from mother liquor or filtrates.
Must use approved procedures and specifications.
Recovered solvents may be reused in same process or in different process if confirmed to meet appropriate standards.
Fresh and recovered solvents and reagents if confirmed their adequacy
1. No approved procedures
2. Specs – carry over impurities
3. Not adequately tested
4. Use not documented
1. Approved procedures
2. Suitable specs
3. Adequate testing
5. Use documented

35. Review of some ICHQ7A’s concepts
Prospective validation (≥3 consec batches):
complete before commercial distribution
Current validation (≥3 consec batches):
For API produced infrequently
Batches may be released for commercial distribution after monitoring and testing
Retrospective Validation ( batches):
Only in exceptional cases
For well established process
All batches, including failed ones
Validation (section 12)
Applies to
Analytical methods
Process
Cleaning
Computerized systems
Validate operations critical to the quality and purity of the API
Periodic review of validated systems

36. ICHQ7A : Conclusion ICH Q7A is a “What to do document”
“How to do” is sometimes described
Flexibility
If necessary, when appropriate …
“Should” even if it could be interpreted mostly as “must”
Emphasis on the risks of
Contamination and cross contamination
Mix-ups, build-up and carry-over of degradants
Lack of traceability

37. WHO GMP and Inspection of API manufacturers
Trends . . .

38. WHO GMP and Inspection of API manufacturers 2002 - 2009
2002 to 2009
India (34)
China (9)
S. Korea (1)
Vietnam (1)

39. WHO GMP and Inspection of API manufacturers
Most API inspections were conducted in India followed by China.
The number of China API sites inspected has increased of recent

40. WHO GMP and Inspection of API manufacturers
Number of inspections per year
API inspections have been increasing over time.
Most API inspections were conducted in 2005, 2006, and 2009.

41. WHO GMP and Inspection of API manufacturers
Inspections (disease areas) and number of observations
Most observations were observed in sites for TB APIs and these were the sites with most of the major observations.
Although sites for Malaria APIs had equally high number of observations, most of them were not major.
The sites for HIV APIs were generally in a reasonable shape.

42. WHO GMP and Inspection of API manufacturers
The most frequently found deficiencies were:
Material management
SOPs
Cleaning
Others included:
Batch records
Labelling
Cross contamination

43. Summary and Conclusions
Inspection of API sites is part of the WHO-PQ procedures
International norms and standards are used during WHO-PQ inspections
Risk management principles are applied when:
scheduling inspections
conducting inspections
closing out inspections
Inspections of API sites has increased over time. Most of the API sites inspected by WHO-PQ are in India and China
Deficiencies have been observed mainly in:
Material management, SOPs, Cleaning, Batch records, Labelling, Cross contamination
Most deficiencies have been observed on sites for TB and Malaria APIs.
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