WHO GMP & API inspections - WHO/OMS: Extranet Systems · PDF file · 2016-06-13WHO GMP and API Inspections Mr. Deus K Mubangizi Technical Officer ... Inspection Cooperation Scheme

Slide 1 of 51Meeting with manufacturers, 5 April 2011

Centre International de Conférences (CICG), 17 Rue de Varembé, Geneva, Switzerland

WHO Prequalification Programme: Priority Essential Medicines

WHO GMP and API InspectionsMr. Deus K Mubangizi

Technical [email protected]



In this presentation:

• WHO-PQ API inspections

– Norms, standards, procedures and process

– Risk-based approach and transparency

• WHO-GMP for APIs: review of some concepts

• WHO-PQ API inspections: Observed trends and review of some deficiencies

• Summary and conclusions



Inspection of API manufacturing sites:

put in perspective.

• Chris Joneckis, Ph.D., senior adviser for chemistry, manufacturing and controls (CMC) issues, noted that:– "quality, safety and effectiveness must be designed and built

into the product. Quality cannot be inspected or tested into the finished product."

• http://www.entrepreneur.com/tradejournals/article/154459079.html

• Ensuring the quality of the API greatly contributes to achieving the objective of building the quality, safety and efficacy into the product. – Inspection of API manufacturing sites is to assess compliance

with Good Manufacturing Practices, and to verify data submitted in product dossiers and APIMFs.



WHO Prequalification: Inspection activities

Prequalification

WHO route SRA* route

Dossier Q/E GMP/GCP Innovators Generics

Simplified procedurePQPQ

PQ

*Stringent Regulatory Authority

APIs,FPPs

BE/CROs



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).



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

� WHO GMP for APIs: Annex 2, WHO TRS957, 2010: http://whqlibdoc.who.int/trs/WHO_TRS_957_eng.pdf#page=144

�Data verification – data manipulation, falsification, (validation,

stability, clinical, bioanalytical)

� Quality control (QC, BAL, NQCL, IQCL)



Guide to Manufacturer Risk ClassificationRef: SOP 401.1: Inspection Frequency and Scheduling

�CROs

�QC Laboratories

�Other non-sterile APIs

�

Non-sterile APIs where there is a special risk (e.g. isomerism, polymorphism, special risk of harmful impurities, etc)

�Sterile APIs

APIs:

�Non-sterile finished products

�Sterile finished products

Finished Products:

LOWMEDIUMHIGHCRITICAL

RELATIVE RISK CATEGORY

PRODUCT TYPE / ACTIVITY



RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN

THE WHO PREQUALIFICATION PROGRAMME

(1 of 2)

Number of

Products

Present in

Product

(Ref. Nos.)

Manufacturer

API

NYFermentation7

NYSterile6

Low riskHigh RiskImpurities5

Low riskHigh RiskSolvents4

Not complexComplexSynthesis3

HighLowSolubility in water2

NYPolymorphism1

Risk ScoreRisk = 1Risk = 2Parameter



RISK ASSESSMENT FORM FOR ACTIVE PHARMACEUTICAL INGRADIENTS WITHIN

THE WHO PREQUALIFICATION PROGRAMME

(2 of 2)

Total Risk Score

PositiveNegative

Site compliance information

(WHO/EDQM/USFDA/Oth

er)

12

Other property consideration11

Low riskHigh RiskParticle size10

Low riskHigh RiskActivity/potency9

LowHighToxicity8

Risk ScoreRisk = 1Risk = 2Parameter

Low

Medium

High

Inspection prioritization

Not

Compliant

CompliantOutcomeLast inspection date

General remarks:



Guide To Inspection Frequency (in months)Ref: SOP 401.1: Inspection Frequency and Scheduling

Determine on a case by case basis

243648Low (L)


182436Medium

(M)


152030High (H)


121824Critical (C)

BasicSatisfacto

ryGood

Unacceptable

Acceptable:

GMP Compliance Rating:RISK

CATEGORY:



Inspection Duration Guide (on-site days)Ref: SOP 401.1: Inspection Frequency and Scheduling

22232334Standard

22333344Major

23343345Large

Re-inspectionInitial

Inspection

LMHCLMHC

RISKManufacturer

Size



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



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.



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 for APIs.

– 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 for APIs 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 for APIs guidelines.

– Another inspection will be required



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.



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.http://www.who.int/medicines/areas/quality_safety/q

uality_assurance/production/en/index.html

• WHO GMP for APIs: Annex 2, WHO TRS957, 2010:http://whqlibdoc.who.int/trs/WHO_TRS_957_eng.pdf#page=144

• WHO GMP: water for pharmaceutical use. 39th Report. Geneva, WHO, 2005 (WHO TRS, No. 929), Annex 3. http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf



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.

http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf

• 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.


• WHO Good Practices for Pharmaceutical Quality Control Laboratories. 44th Report. Geneva, WHO, 2010 (WHO TRS, No. 957), Annex 1.

http://whqlibdoc.who.int/trs/WHO_TRS_957_eng.pdf#page=95

USPBP

Ph. Eur.Ph. Int.

Other guidelines

e.g. ICH, ISO



WHO GMP for APIs = ICH Q7same numbering of sections

WHO GMP for APIs = ICH Q7same numbering of sections

• I. INTRODUCTION

• 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



WHO GMP for APIs: Key definitions

• 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.



• From what point does WHO GMP for APIs start to be applied ?– WHO GMP for APIs applies from the point at which

production of the API begins – the point at which the API starting material is introduced in the API manufacturing process”.

– Some indications are provided in Table 1 of WHO GMP for APIs.• 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.

WHO GMP for APIs: Introduction



WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers

Increasing GMP requirements



Main issue : How to define the API SM ?

Only flow chart

GMPs do not

apply

Detailed description

GMPs apply

Competent

Authorities

Industry

API SM

RM (solvent, catalyst, reagent, filtration aid,

decolorizing agent, chromatography phase, etc.)

C, H, O, N SM (Intermediates)n Active substance

crude

Active substance

(pure)



Application of WHO GMP for APIs

• Companies should decide at which point WHO GMP for APIs 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.



Designation of API starting material

• API starting material:

– Is incorporated as a significant structural fragment into

the structure of the API.

– it is obtained by commonly known procedures.

– it is a compound whose name, chemical structure,

chemical and physical characteristics, properties and

impurity profile are well defined

– it is commercially available

– at least two synthetic steps are required between the

starting material and the API.



Incorporated as a significant structural fragment into the structure of the API.

• Example of Zidovudine: β-thymidine versus

sodium azide

β-thymidine sodium azide Zidovudine

SM??



At least two synthetic steps between the starting material and the API:For Levofloxacin: Which one is incorporated as a significant structural fragment

into the structure of the API

SM??

2 synthesis steps 2 synthesis steps Levofloxacin



At least two synthetic steps between the starting material and the API:For Artemether and Artesunate: Artemisinin versus Dihydroartemisinin

Artemisinin Dihydroartemisinin

Artemether

Artesunate

SM??



• Quality management (Chapter 2)

– 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)

Review of some WHO GMP for APIs concepts



• Facilities,equipment and utilities system

– Facilities designed to prevent mix-

ups and contamination (sec 4.11)

– Precautions implemented based on

a risk assessment

– Equipment cleaning methodology

and intervals appropriate to prevent

build-up and carry-over of

contaminants (degradants)

(sec.4.15)


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



• HVAC systems (section 4.2)

– Adequate ventilation, air filtration and exhaust systems should be provided where appropriate (sec 4.21, 4.22)

– Qualification and appropriate monitoring and operating range limits in place (sec 4.20)

• Water (section 4.3)

– WHO potable water quality as a minimum(sec 4.31)

– Water for final isolation and purification steps for API for sterile products: test for microbial counts, objectionable counts and endotoxins (sec 4.34)




Inspection of API manufacturers

• Cross-contamination: Centrifuge XZ1234 labelled as

clean was found with white residues between the

basket and the inner wall

• Double standards:

– Block A (announced): The status of all centrifuges was

indicated and the centrifuge cloths were brand new and

identified as dedicated to centrifuges and stages of

synthesis;

– Block B (unannounced): The status of centrifuge XZ4567

was not indicated and all the centrifuge cloths were found

to be old and not dedicated to centrifuges and stages of

synthesis.



• Material management (section 7.)– At least, identity testing of each batch on a

sample representative of the batch (sec 7.30)

– Reduced testing for approved/validated

suppliers (sec 7.31)

• Past quality history

• Full analysis at least on three batches before

starting reduced-testing

• Reliability of the CoA checked at regular

intervals

– Precaution for bulk deliveries in non-dedicated

tankers (sec 7.22) – Certificate of cleaning

Testing for trace impurities, supplier audit.




WHO GMP and Inspection of API manufacturers

Inappropriate material handling e.g.:

• The warehouse temperature was monitored but not controlled. It reached 34°C even as some materials were required to be stored in “a cool and dry place”.

• Several drums were marked as sampled and approved, although the drums were still sealed.

• Several drums (6) of the same approved batch of ABC were noted with a broken seal – no "sampled" label.

• Labels affixed on drums were dirty, torn, and unreadable.




Other examples of non-compliances

• Sampling and storage of materials

– The number of drums sampled for a consignment of 340 drums of ABC B. No. 123 as recorded on the sampling sheet (5) was less than that required by the sampling procedure (√N+1 = 19).

– ABC BN 123 was stored in an uncontrolled T° storage area (same warehouse where staff bus was parked). The recommended storage condition for this material is below 150C

– API XYZ B. No. 1111 had a release status label dated 09.02.2008 although its manufacturing date was 10.02.2008.



• Production (section 8)– Critical operations should be witnessed

or subjected to an equivalent control (sec 8.12)

– Deviations should be documented, explained and/or investigated (sec 8.15)

– Process time limits should be respected (sec 8.20)

– Conditions and duration of storage of intermediates (sec 8.21)

– In-process sampling and controls (sec 8.3)

• approved written procedures, avoid risk of cross contamination during sampling, sample integrity




Review of some concepts of WHO GMP for APIs

• 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 size2. Blending tailings

APIs for OSDs/ Suspensions

1. Particle size distribution2. Bulk density3. Tap density



• 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


• Reprocessing or reworking for intermediates or APIs

which do not conform to standards or specifications




• Recovery of Materials and

solvents (sec 14.4)

– 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. Approved procedures2. Suitable specs3. Adequate testing5. Use documented

1. No approved procedures2. Specs – carry over impurities3. Not adequately tested4. Use not documented




• Deficiencies related to recovered solvents:

– specifications for recovered solvents (Ethanol, Toluene, Ethyl acetate, Triethylamine, methanol, Isopropyl alcohol) from and reused in various stages of synthesis allowed low purity and high maximum single unknown impurity which were not justified by actual data.

• e.g. specification for recovered methanol: potency as NLT 90.0% and MSUI as NMT 10.0%, the results showed potency of NLT 98% and MSUI on NMT1%.

– No ratio for fresh to recovered solvents had been set for the above solvents based on validation data.

– No limit had been set on the number of times/cycles the above solvents could be recovered and re-used – risk of impurity build up.



• 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


1. Prospective validation (≥≥≥≥3 consec

batches):• complete before commercial

distribution

2. Current validation (≥≥≥≥3 consec

batches):• For API produced infrequently• Batches may be released for

commercial distribution after monitoring and testing

3. Retrospective Validation (10 - 30

batches):• Only in exceptional cases• For well established process• All batches, including failed ones




• Data Manipulation:

– The calibration report for the T° sensor

supporting the “OK” status written on the

qualification report of reactor R1234 carried out in

March 2009 was requested on December 9th by

the inspector and presented the day after in the

morning. This calibration report was dated March

2009 although the form presented by the

company was effective in July 2009. Company’s

management acknowledged that this document

was created after the inspectors’ request.



ChangeChange 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 controcontroll

– Proposal drafted,

reviewed and approved

by the appropriate

organisational unit

– Change reviewed and

approved by QU

– Classification and impact

assessment

– Evaluation and

monitoring + Notification




– Contract manufacturers (section 16)

• Contract manufacturers should comply with

GMP (sec 16.10)

• A contract or a formal agreement should exist

between the contract acceptor and the contract

giver (sec 16.12).


– Personnel (section 3)

• Appropriate and regular GMP

training periodically assessed

(sec 3.12)



WHO GMP and Inspection of API manufacturersWHO GMP and Inspection of API manufacturers



0

20

40

60

80

100

120

140

No

of

sit

es

Type of API

INSPECTION STATUS OF API SITES USED IN PRODUCTS UNDER WHO

PREQUALIFICATION

Not yet Inspected 20 15 8 3 0 0 0 0 0 0 46

Innovators/PICS 33 3 8 5 0 0 0 0 0 0 49

Sites inspected - NC 1 4 1 0 0 0 0 0 0 0 6

Sites inspected - C 10 5 4 0 0 0 2 2 1 1 25

HA TB MA RH IN D HA, IN HA, TB HA, MAHA, MA,

TBTotal

Out of 126 API sites participating in PQ activities, 49 were accepted based on approval by PICS inspectorates.



Most of the API sites were located in India and China and that where most of the inspections have taken place.

0

20

40

60

80

100

120

140

Num

ber of sites

Baham

as

Belg

ium

Canada

Chin

a

Fra

nce

Germ

any

India

Irela

nd

Italy

Japan

Latv

ia

Mexic

o

Neth

erlands

Port

ugal

Puert

o R

ico

Sin

gapore

South

Afr

ica

South

Kore

a

Spain

Sw

itzerland

Thailand

United K

ingdom

USA

Vie

tnam

Tota

l

Host countries of API sites

Host Countries for API Sites within the WHO Prequalification of Mediucines Programme

Not yet Inspected

Innovators/PICS

Inspected & NC

Inspected & C



The sites inspected are those producing many APIs (average 4 APIs per site) mainly for HIV/AIDS, TB and MA in that order.

APIs PER SITE

0

2

4

6

8

10

12

Inspection Status of API Sites

No o

f A

PIs

per Site

Average 4 2 1 1 2

Minimum 1 1 1 1 1

Maximum 10 2 3 5 10

Sites inspected - C Sites inspected - NC Innovators/PICS Not yet Inspected All sites



The sites inspected were the ones producing APIs used in most FPPs (average

each API site representing 21 FPPs). This demonstrates maximizing use of

available inspection resources.

NUMBER OF FPPs USING APIs FROM EACH SITE

0

10

20

30

40

50

60

70

80

90

Inspection Status of API Sites

No o

f FP

Ps p

er A

PI S

ite

Average 21 15 3 2 7

Minimum 1 2 1 1 1

Maximum 80 48 12 10 80

Sites inspected - C Sites inspected - NC Innovators/PICS Not yet Inspected All sites



Trends from WHO-PQP Inspection of API manufacturers


0

5

10

15

20

25

30

35

40

Ave (total) obs per

site

Ave (Major)

TB

HIV/AIDS

MAL

• 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.

2007 -2009. Inspections (disease areas) and number of observations





• The most frequently

found deficiencies

were:

– Material management

– SOPs

– Cleaning

• Others included:

– Batch records

– Labelling

– Cross contamination

0

1

2

3

4

5

6

7

8

9

10

Major deficiencies

Crosscontamination

Batch records

SOPs

MaterialManagement

Cleaning

Labeling



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

• Emphasis on the risks of

– Contamination and cross contamination

– Mix-ups, build-up and carry-over of degradants

– Lack of traceability

• 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.

谢谢谢谢谢谢谢谢！！！！

ध�यवादध�यवादध�यवादध�यवाद

Dhan'yavāāāāda

Documents

WHO GMP & API inspections - WHO/OMS: Extranet Systems · PDF file · 2016-06-13WHO GMP and API Inspections Mr. Deus K Mubangizi Technical Officer ... Inspection Cooperation Scheme