WHO GMP auditing / inspection

Arvind Kukrety
Deputy Drugs Controller (India) Office of Deputy Drugs Controller (India),
Central Drugs Standard Control Organization (CDSCO),
Ministry of Health & Family Welfare, Govt. of India,
www.cdsco.gov.in

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 Outline
WHO GMP certification
Scheme
WHO GMP norms
 Technical requirements
Inspection approaches
Inspection planning and report
Risk rating system
 WHO GMP certification scheme
 WHO expert committee on specification for
pharmaceutical preparations met in Geneva from
10-15 December 1990.
 WHO Certification Scheme on the Quality of
Pharmaceutical Products Moving in International
Commerce, which provided a simple administrative
procedure that enabled importing countries to
obtain information on the registration status of a
product in its country origin and to obtain a
declaration that the manufacturing facility had
been inspected and was operating in compliance
with WHO’s requirements for good manufacturing
practices (GMP).
 WHO GMP certification scheme
 WHO-TRS No. 823, 1992 Page No. 99 – 100
Proposed guidelines for implementation of the WHO
Certification Scheme on the quality of Pharmaceutical
Products moving in International Commerce
 WHO-TRS No. 863, 1996 page No. 155 – 172
Guidelines for implementation of the WHO Certification
Scheme on the quality of Pharmaceutical Products moving in
the International market
 The Format and Procedures to issue COPP are
recommended by WHO as per the following Guidelines;
a) WHO-TRS No. 823, 1992 page No. 99 – 100
b) WHO-TRS No. 863, 1996 page No.155 – 172
c) WHO-TRS No. 908, 2003 page No. 90 – 93
 DCG (I) notice for timelines (4.3.2020)
• DCGI circular on disposal of application of WHO GMP issued on 04.3.2020
• Compliance to applicable WHO Technical Series Report (TRS)
• Disposal within 21/28 days and issue of certificate within 5 days.
• Inspection as per 47th DCC meeting – SOP and self appraisal checklist.
Checklist for Screening the Documents related to COPP
DCG (I) notice 6.2.2017 for Risk based Inspection
Prescribed formats (23.4.2016)
Model certificate for CoPP
Model certificate for CoPP
Model certificate for GMP
 WHO Technical Report Series
Sr. TRS No. Title Thrust of the guidance
No. (Year)
1 Annexure-2 Guidelines on heating, Designing of HVAC system, building design and
TRS 1019 ventilation and air- layout of areas, air-handling units (AHUs),
(2019) conditioning systemscomponents in AHUs, room pressure, pressure
for non-sterile
differentials, pressure cascades, levels of
pharmaceutical filtration, humidification, dehumidification,
products and heating and cooling of air.
2 Annex 3 TRS Good manufacturingValidation of heating, ventilation and air-
1019 (2019) practices: guidelines
conditioning systems, Validation of water
on validation systems for pharmaceutical use, Cleaning
validation, Analytical procedure validation,
Validation of computerized systems, Guidelines
on qualification , Non sterile process validation
3 Annex10 TRS Stability testing of Active pharmaceutical ingredient (API) and
1010 (2018) active pharmaceutical finished product Stress testing, Selection of
ingredients and batches, Container-closure system,
finished Specification, Testing frequency, Storage
pharmaceutical conditions, Stability commitments, Evaluation,
products Statements and labeling, Ongoing stability
studies
 WHO Technical Report Series
Sr. TRS No Title Thrust of the guidance
No. (Year)
Annexure-4 Hold Time Study Justification of storage time of intermediate
4
TRS 992 drug processing. Protocol and report.
(2015)

Annexure-2 WHO good Pharmaceutical quality system- Quality Risk

5
TRS 986 manufacturing practices Management (QRM), Product quality Review
(2014) for pharmaceutical (PQR), quality audits, Good practice in
products: main principles production and quality control.
Annexure-2 WHO guidelines on Principles of quality risk management, Quality
6
TRS 981 quality risk management risk management process, QRM application
(2013) for pharmaceuticals.

Annexure-2 WHO good Pharmaceutical water production, storage and

7
TRS 970 manufacturing practices: distribution system as per indented use.
(2012) water for Includes Pure Steam Generation (PSG)
pharmaceutical use
Annexure-2 WHO good practices for Environment, sterility testing facility,
8
TRS 961 pharmaceutical Reagents and culture media.
(2011) microbiology
laboratories
 WHO Technical Report Series
Sr. TRS No. Title Thrust of the guidance
No. (Year)
9 Annexure-6 WHO good manufacturing Focus on manufacture and sterilization of
TRS 961 practices for sterile sterile/aseptic preparations, processes
(2011) pharmaceutical products and its validation.
10 Annexure-13 WHO guidelines for Quality management system in Lab.
TRS 961 preparing a laboratory
(2011) information file
11 Annexure-14 WHO guidelines for Details of Quality management,
TRS 961 drafting a site master Personnel, Premises and equipment
(2011) file
12 Annexure-1 WHO good practices for Quality management system, Calibration,
TRS 957 pharmaceutical quality verification of performance and
(2010) control laboratories qualification of equipment, instruments
and other devices, Working procedures
and Validation of analytical procedures.
Data integrity
13 Annexure-2 WHO good manufacturing Quality management system, Buildings
TRS 957 practices for active and facilities, Specific guidance for APIs
(2010) pharmaceutical manufactured by cell
ingredients culture/fermentation
 WHO Technical Report Series
Sr. TRS No. Title Thrust of the guidance
No. (Year)

14 Annexure-4 WHO guidelines for Sampling process, Sampling plans for starting
TRS 929 sampling of materials, packaging materials and finished
(2005) pharmaceutical products product.
and related materials
15 Annexure-6 Guidance on Good Content of report, observations and
TRS 908 Manufacturing Practices Conclusions
(2003) (GMP): inspection report
16 Annexure-9 Guide to good storage Premises and facilities, Storage requirements
TRS 908 practices for
(2003) pharmaceuticals

17 Annexure-9 Guidelines on packaging Requirement of Packaging materials and

TRS 902 for pharmaceutical closures, Quality assurance aspects of
(2002) Products packaging, Quality specifications
Why Good manufacturing Practices Required
Pharmaceutical product life cycle approach
Good Manufacturing Practices for APIs (TRS 957)
Quality management Personnel Buildings and Process equipment
facilities
Documentation and records Materials management Production and in-process controls
Packaging and identification labeling of APIs and Storage and distribution
intermediates
Laboratory controls Validation Change control
Rejection and reuse of Complaints and recalls Contract manufacturers (including
materials laboratories)
Manufacture of sterile preparations (TRS 961)
For manufacturing, four grades of clean areas are distinguished:-
• Grade A: for high-risk operations, e.g. filling and making aseptic connections
• Grade B: In aseptic preparation, this is the background environment for the Grade A zone
• Grades C and D: where the product is not directly exposed

Sterilization
• Terminal sterilization
• Sterilization by filtration
 Aseptic processing - Media fill simulation-
• For small batches the number of containers for media fills should at least equal the size of
the product batch. The target should be zero growth and the following should apply:
• when filling fewer than 5000 units, no contaminated units should be detected.
• when filling 5000–10 000 units: — one contaminated unit should result in an investigation, including
consideration of a repeat media fill;
• two contaminated units are considered cause for revalidation following investigation;
• when filling more than 10 000 units: — one contaminated unit should result in an investigation;
— two contaminated units are considered cause for revalidation following investigation.
Pharmaceutical Water System (TRS 970)
 Material of construction  Storage vessel requirements
(MOC): Materials that come  Water distribution pipework/loops
into contact with systems for  Temperature control and heat
water for pharmaceutical use exchangers
 Compatibility  Circulation pumps
 Prevention of leaching  Bio-contamination control techniques
 Corrosion resistance  Operational considerations: Start-up
 Materials: SS grade 316 / 316L and commissioning of water systems
or a higher grade of stainless  Qualification: (DQ, IQ, OQ, and PQ)
steel  Validation:
 Smooth internal finish: surface  Phase 1: Sample daily or continuously
monitor (Two weeks). Water is not
roughness of not greater than used for "finished pharmaceutical
0.8 micrometre (Ra). product (FPP) manufacturing during
this period.
 Joints: Design of Flanges, unions
 Phase 2: (Two weeks)
and valves.
 Phase 3: (One year)
 Documentation.  Continuous system monitoring
 System sanitization and  Maintenance & System review
bioburden control (Trend analysis)
 Cleaning Validation (TRS 1019)
The objective of cleaning validation is to prove
that the equipment is consistently cleaned of
product, detergent and microbial residues to an
acceptable level, to prevent possible
contamination and cross-contamination

Cleaning criteria:
Visually clean
10 ppm in another product
0.1% of therapeutic dose
Initiate CAPA
Verify / Validate

Define
Problem Implement

Solution Conduct
(Action Plan) Effectiveness Check

Investigate Cause Close CAPA

 GMP – Schedule M and WHO
Sr. Attributes Schedule M WHO GMP
No.
1 Main Principle of Good
Yes – Control on contamination, Yes – additionally Annual product
manufacturing practices cross contamination, mix-ups, review, Quality management
and consistency of quality system, quality risk management
(validation) and product life cycle approach.
2. Guidelines of sterile products and Yes Yes. For API -More focus on
API Key Starting Materials (KSM)
and requirements for
fermentation based products
3 Specific requirements for Tablet, Yes No
capsule, Liquid, External preparation
etc and Equipment / area
requirements.
4 GMP requirement for Biologicals No Yes
5. Guidance document on Sampling, No Yes
Good distribution Practices, Quality
Risk management (QRM) data
integrity, Qualification &
Validation-cleaning, analytical
method, process validation, HVAC,
water system etc.
6 Specific guidelines on Stability For new drugs Yes
studies.
7. Guidance on change control No Yes
(Variation), data integrity,
 How Quality is Monitored
 Pre-licensing Control:  Whether the firm know their
product well?
 Plan approval, test licensing,
 Quality by Design, control on input,
 Establishment / product outputs, critical control points
licensing, testing  Whether the firm know their
 Post Licensing Control: process well?
 Design, adequacy of facility and system.
 Periodic inspections / change in
facility and key personnel  How the firm maintains
approval consistency?
 Validations and its status
 Post marketing
 Whether the firm have adequate
surveillance: controls?
 Sampling, NSQ investigations,  Monitoring of
administrative and penal actions  How the firm control changes?
 Pharmacovigilance / Hemo-  How data is maintained and
vigilance preserved
 Verifiable data.
 Inspection Process
 Application to SLA and CDSCO– Data of the individual
product, SMF etc. as per checklist
 Assessment – desk inspection / risk assessment
 Completeness of application
 Technical Review (Site Master File, CMC, changes in
facility, technical staff etc.)
 Risk review – Number of products, size of facility, type
of product, past inspection findings & compliance,
NSQ reported, complaints, Adverse events etc.
 Planning for joint inspection
 Notification of inspection (SLA/CDSCO)
 Inspection for verification
 Inspection Process Contd….
 Inspection 2-3 days focusing all critical areas- use
of checklist / aid memoir using risk based approach
 Documentation – Change Control, OOS, CAPA, Validation,
Product/process characterization, consistency, SOPs ,
Personnel & training, etc.
 Aseptic processing and sterilization,
 System and Facility -Including service and ancillary areas
 Exit meeting
• Manual for operation in
 Inspection Report CDSCO Zones, Sub-
 Review by superior zones and Port office
 Letter for Compliance • SOPs for inspection and
reporting
 Review of compliance
 Final action
 Content of report
 Manufacturer Details -Name, address, license details,
products manufactured, key personnel involved.
 Inspection Details- Past & current inspection dates,
type & scope, GMP guidelines followed, Inspection team
 Introduction-Brief of activity, outsourcing, any
limitation, summary of changes, brief of quality system.
 Findings (factual) & Discussion-observations,
deficiencies, categorization (critical, major, minor)
 Remarks and Recommendation
 References & Appendix
Inspection process-Way forward
Biological products – Vaccine and rDNA products
Intrinsic Risk Matrix (based on complexity and criticality of site)

Compliance risk (Non conformances observed – Critical, Major, Minor)

Compliance risk

Risk Rating Matrix

Inspection process-Way forward

Frequency of inspection based on RISK RATING

 Risk rating – illustration (Intrinsic risk)
Name of the manufacturer M/s. XXXXXXXX
Products Manufactured:
• Vaccines (viral, bacterial, Live an inactivate)
• Water for injection various sizes

• Firm manufactures biologicals having complex

manufacturing process and produce ascetically.

Criticality
Complexity 1 2 3
1 1 (Low) 2 (Low) 3 (Medium)
2 2(Low) 4 (Medium) 6 (High)
3 3 (Medium) 6 (High) 9 (High)
 Risk rating – illustration (inspection outcome)
S.No Observation Category
.
1 On review of BMR of product VVVVV having the Batch no XXXXXX, it was Major
observed that firm has used API had the expiry date of x/21 and formulation
has the expiry date of XX/23 . In the justification firm has provided the real
time study in which the product is 32 month stable and as per accelerated
stability studies it’s stable for 17 month. Firm needs to provide suitable
justification in this matter with respect to provision of Drugs and Cosmetics
Rules. The firm Could not produce any approval of such usage from CLAA/SLA
2 It is observed that the Drug Substance for Component I, Batch No. XXXX Major
does not complies as per vendor COA for the test of specific activity. Still the
firm has used same batch for manufacturing of finished batches (Component
I) i.e XXXX1, XXXX2, XXXX3. All the three batches failed in identification.
The firm could not justify using OOS material.
3 As per specification no. XXXXX & YYYYY for the testing of Component I and Major
Component II, the firm has performed in house test for specific activity only
(Spectrophotometric method) on xxxxxx and has not performed other critical
test like xxxxx and yyyyy by ELISA.
 Risk rating – illustration (inspection outcome)
4 The firm has shown the technology transfer for the product CCCCC Major
through R&D, however report does not show involvement of the R&D
team for technology transfer
5 The firm has performed the 13 point risk assessment for availability of Minor

the nitrogen line at user point in line-1 (filling line) as per risk assessment
document no. XXXXXXX. Out of 13 points, 12 identified failures have RPN
between 28 to 50 for which CAPA is required as specified in the risk
assessment document no. XXXXXX. It is observed that the firm has not
followed their procedure.
6 The firm is required to add non-routine intervention at point no. 4 Minor
(Machine parts adjustment) of the protocol XXXXX to consider pre and
post needle movement for nitrogen gas purging during pooling and filling
simulations (medial fill trial) for vial presentations.
7 Physical and environment monitoring parameters is not mentioned in BPR Minor
of Batch No. YYYY of product XXXXX
 Risk rating – illustration (inspection outcome)

8 Epoxy flooring of the Cold Storage room (-20℃, Id. No. Minor
WWWW) found completely broken / damaged. The firm could not
explain why no action has been taken for its correction.
9 The firm was found not performing the GPV (Gradient Minor
proportioning valve) test in the calibration of HPLC instrument. It
is also observed that the firm is performing flow rate calibration
at 1 ml flow only. The firm is required to cover the appropriate
range for the parameter flow rate calibration of HPLC instrument.
10 As per the SOP for stabilities studies (doc no. CCCC) the firm has Minor
loaded the samples for stability testing immediately after final
packing. It is observed that for product XXXXX, batch no.
XXXXX, M/D VV was loaded in accelerated condition (2-8℃) on
XXXXX i.e after 7 days after final packing. This deviation from
SOP could not be explained.
 Risk Identification
Date(s) of inspection : XXXXX

Total Observations: 10
Number of Critical Observations: Nil

Number of Major Observations: 04

Number of Minor/other Observations: 06

Whether Major Observation are more than 05: No

Compliance submission date: XXXXXX

Number of Critical Observations Closed: NA

Number of Critical Observations still open: NA

Number of Major Observations Closed: NIL

Number of Major Observations still open: 04

Number of Minor Observations Closed: 04

Number of Minor Observations still open: 04

 Compliance Risk (Non Conformances observed- Critical, Major,
Minor)
Deficiency Profile Compliance-related Risk Score
1 or more Critical Deficiencies or more than 5 High
major Deficiencies
From 1 to 5 Major Deficiencies Medium
No Major or Critical Deficiencies Low

Risk Rating matrix

Intrinsic Risk
Compliance Risk Low Medium High
Low Risk Rating = A Risk Rating = A Risk Rating = B
Medium Risk Rating = A Risk Rating = B Risk Rating = C
High Risk Rating = B Risk Rating = C Risk Rating = C

Risk Rating Suggested Inspection Frequency

A Reduced Frequency, 2 to 3 Years

B Moderate Frequency, 1 to 2 Years
C Increased Frequency, < 1 Year
 Summary
 Inspections begins with desk review-
criticality and risk assessment
Inspector to be equipped with adequate tools
to assess lifecycle of the product
Inspections at site for verification
 Risk based approach during review as well
as Inspection
Rational ensuring inspection outcomes (Risk
rating system)
Thanks for your attention
[email protected]

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