GMP & Validation

Alfa Laval Pharma Seminar, March, 2006, India

Per-ke Ohlsson
Alfa Laval, ESE

Validation
Validation is a documented program providing a high
degree of assurance that a process/system consistently
meets pre-determined specifications
Defined by the Food and Drug Administration (FDA)

i.e. if the required activities have not been properly

documented, then they have not been performed.

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Why Validation?
To prove that the processes works (consistently and for
its intended use) before starting manufacturing.

To prove that the processes fulfils GMP in order to get

acceptance from authorities to start manufacturing.

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Authority Guidelines

Commissioning
Qualification
Validation

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Definition Validation
Establishing documented evidence which
provides a high degree of assurance that a
specific process will consistently produce a
product meeting its pre-determined
specifications and quality attributes*

*FDA Guidelines on General Process Validation May 1987

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Definition Qualification
The documented verification that all aspects of
a facility, utility, or equipment that can affect
product quality; IQ, adhere to approved
specifications and are correctly installed, OQ,
operate as intended throughout all anticipated
ranges, PQ, perform as intended meeting
predetermined acceptance criteria*
*ISPE Baseline Pharmaceutical Engineering Guides for New and Renovated Facilities
Volume 5: Commissioning and Qualification March 2001

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Definition Commissioning
A well planned, documented, and managed
engineering approach to the start-up and
turnover of facilities, systems, and equipment
to the end-user that results in a safe and
functional environment that meets established
design requirements and stakeholder
expectations*
*ISPE Baseline Pharmaceutical Engineering Guides for New and Renovated Facilities
Volume 5: Commissioning and Qualification March 2001

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V-Model Direct Impact Systems

Commissioning

Qualification

PQ Test Plan

URS

PQ

OQ Test Plan
(incl. FAT)

FS
DS

FAT
Impact assessment

IQ Test Plan
(incl. PDI)

OQ
IQ

Validation
Process Validation
Cleaning Validation
Revalidation

SAT

Implementation
ISPE Baseline Guides Volume 5: Commissioning and Qualification March 2001

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PDI: Pre Delivery Inspection

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Impact Assessment
Direct Impact Systems have a direct impact on
product quality
Indirect Impact Systems are linked to a Direct
Impact System
No Impact Systems do not have any impact
and are not linked to a Direct Impact System
ISPE Baseline Guides Volume 5: Commissioning and Qualification March 2001

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V-Model Indirect Impact Systems

Commissioning
URS

General testing

Commissioning plan
FAT

FS
DS

PDI

Performance
Testing

Validated
indirectly via
the direct
impact system

Regulation &
Adjuctment testing
Physical completion
& Inspection

Impact assessment

Implementation
ISPE Baseline Guides Volume 5: Commissioning and Qualification March 2001

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Commissioning
User Requirement Specification
should define what the process is
required to do

URS

Functional Specification should define

how the process meets the
requirements defined in the URS

FS

Design Specification should define how

the process should be designed to meet
the specifications in the FS

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PQ

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DS

OQ
IQ

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Qualification
URS

PQ

FS
DS

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OQ
IQ

Performance Qualification verify

that the process perform effectively
and reproducibly
Operational Qualification verify that
the process operates as intended
throughout the operating range
Installation Qualification verify that the
process are correctly installed

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Process Validation
FDA Guidance
http://www.fda.gov/ora/inspect_ref/igs/

European Guidance
http://pharmacos.eudra.org/F2/eudralex/vol-4/home.htm

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FDA Guidance
BIOTECHNOLOGY

BIOTECHNOLOGY INSPECTION GUIDE (11/91)

DRUGS

BULK PHARMACEUTICAL CHEMICALS (9/91)

HIGH PURITY WATER SYSTEMS (7/93)
LYOPHILIZATION OF PARENTERALS (7/93)
MICROBIOLOGICAL. PHARMACEUTICAL QUALITY CONTROL LABS (7/93)
PHARMACEUTICAL QUALITY CONTROL LABORATORIES (7/93)
VALIDATION OF CLEANING PROCESSES (7/93)
DOSAGE FORM DRUG MANUFACTURERS - CGMP'S (10/93)
ORAL SOLID DOSAGE FORMS PRE/POST APPR. ISSUES (1/94)
STERILE DRUG SUBSTANCE MANUFACTURERS (7/94)
TOPICAL DRUG PRODUCTS (7/94)
ORAL SOLUTIONS AND SUSPENSIONS (8/94)

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EU-GMP
Annex 15 Qualification and validation
1. Qualification and Validation
2. Planning for Validation
3. Documentation
4. Qualification
5. Process Validation
6. Cleaning Validation
7. Change Control
8. Revalidation

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Validation Types*
Process Validation
Prospective Validation
Concurrent validation
Retroperspective validation

Cleaning Validation
(Change Control)
Revalidation
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*EU - GMP

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Process Validation*
Prospective Validation
Prospective validation should normally be completed prior to
the distribution and sale of the medicinal product
(prospective validation)
It is generally considered acceptable that three consecutive
batches/runs within the finally agreed parameters, would
constitute a validation process.
Batches made for validation should be the same size as the
intended industrial scale batches.

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*EU - GMP

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Process Validation*
Concurrent validation
In exceptional circumstances it may be acceptable not to
complete a validation programme before routine production
starts.
The decision to carry out concurrent validation must be
justified, documented and approved by authorised personnel.
Documentation requirements for concurrent validation are
the same as specified for prospective validation.

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*EU - GMP

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Process Validation*
Retroperspective validation
Retroperspective validation is only acceptable for wellestablished processes and will be inappropriate where there
have been changes in the composition of the product,
operating procedures or equipment.
Batches selected for retrospective validation should be
representative of all batches made during the review period.
For retrospective validation, generally data from ten to thirty
consecutive batches should be examined to assess process
consistency.
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*EU - GMP

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Cleaning Validation*
Cleaning validation should be performed in order to confirm the effectiveness of a
cleaning procedure. The rationale for selecting limits of carry over of product residues,
cleaning agents and microbial contamination should be logically based on the materials
involved.
Normally only cleaning procedures for product contact surfaces of the equipment need to
be validated.
For cleaning procedures for products and processes which are similar, it is considered
acceptable to make a single validation study utilising a worst case approach which takes
account of the critical issues.
Typically three consecutive applications of the cleaning procedure should be performed
and shown to be successful.
Products which simulate the physicochemical properties of the substances to be removed
may exceptionally be used instead of the substances themselves, where such substances
are either toxic or hazardous.

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*FDA Guidance

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Change control*
Written procedures should be in place to describe the actions
to be taken if a change is proposed that may affect product
quality or reproducibility of the process. Change control
procedures should ensure that sufficient supporting data are
generated to demonstrate that the revised process will result
in a product of the desired quality, consistent with the
approved specifications.
The need for, and the extent of, re-qualification and revalidation should be determined.
Note the alternative route with PAT!

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*EU - GMP

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Revalidation*
Facilities, systems, equipment and processes, including
cleaning, should be periodically evaluated to confirm that
they remain valid.
Revalidation is also needed when changes in critical
manufacturing steps or other changes have been done that
has the potential to affect the product quality. This should
have been evaluated in the change control procedure.

Note the alternative route with PAT!

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*EU - GMP

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Underlying guidelines for validation

Differences between Regulation, Guidelines and other information

Document

Definition

Regulation/
Directive

Legal requirements that must be followed

Guideline

Suggestions!, not mandates, more detailed

definitions and expectations

Other
Information
(ICH, GAMP,
ISPE,, etc)

Informal release of information; potential

new regulations or guidelines, new
interpretation, seek industry feedback

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Regulations
GMP the only pharmaceutical regulation covering the
pharmaceutical industry
Approving authority

- EU, US, Japan, WHO, etc.

Regulation

cGMP/
GMP

Pharmaceutical companies
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US - GMP
CFR (Code of Federal Regulation) 21 part 210
Regulations in parts 211 through 226 contain minimum
cGMP for the manufacture, processing, packaging, or
holding of a drug.
Eligible for all drugs manufactured and/or imported into
the US
Failure to comply with any of these regulation shall be
subject to regulatory action
http://www.fda.gov/cder/dmpq/cgmpregs.htm
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US - GMP
CFR 21 parts 210 - 226
Part 210
Part 211
Part 216
Part 225
Part 226

cGMP; General
cGMP for finished pharmaceuticals
Pharmacy compounding
(withdrawn/removed drug products)
cGMP for medicated feeds
cGMP for type A medicated articles

Written by FDA (Food & Drug Association)

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US - GMP
CFR 21 part 211, Table of content
Subpart A General Provisions
Subpart B Organisation and Personnel
Subpart C Buildings and Facilities
Subpart D Equipment
Subpart E Control of Components and Drug Products
Subpart F Production and Process Controls
Subpart G Packaging and Labeling Control
Subpart H Holding and Distribution
Subpart I Laboratory Controls
Subpart J Records and Reports
Subpart K Returned and Salvaged Drug Products
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US GMP
211.63 Equipment design, size, and location.
Equipment used in the manufacture, processing, packing, or holding of
a drug product shall be of appropriate design, adequate size, and
suitably located to facilitate operations for its intended use and for
its cleaning and maintenance.
211.65 Equipment construction.
(a) Equipment shall be constructed so that surfaces that contact
components, in-process materials, or drug products shall not be
reactive, additive, or absorptive so as to alter the safety, identity,
strength, quality, or purity of the drug product beyond the official or
other established requirements.
(b) Any substances required for operation, such as lubricants or
coolants, shall not come into contact with components, drug
product containers, closures, in-process materials, or drug
products so as to alter the safety, identity, strength, quality, or purity
of the drug product beyond the official or other established
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requirements.

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EU - GMP
Chapter 3, Premises and Equipment, Equipment
3.34 Manufacturing equipment should be designed, located and
maintained to suit its intended purpose.
3.35 Repair and maintenance operations should not present any hazard to
the quality of the products.
3.36 Manufacturing equipment should be designed so that it can be easily
and thoroughly cleaned. It should be cleaned according to detailed and
written procedures and stored only in a clean and dry condition.
3.37 Washing and cleaning equipment should be chosen and used in
order not to be a source of contamination.
3.38 Equipment should be installed in such a way as to prevent any risk of
error or of contamination.
3.39 Production equipment should not present any hazard to the products.
The parts of the production equipment that come into contact with the
product must not be reactive, additive or absorptive to such an extent that
it will affect the quality of the product and thus present any hazard.

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EU - GMP
Commission Directive from 13 June 1991 91/356/EEC,
principles and Guidelines of good manufacturing practice
for medicinal products for human use.
Commission Directive from 23 July 1991 91/412/EEC,
principles and Guidelines of good manufacturing practice
for medicinal products for veterinary use.
Written by the European Commission
http://pharmacos.eudra.org/F2/eudralex/vol-4/home.htm

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EU - GMP
Table of content
Basic Requirements
1. Quality Management
2. Personnel
3. Premises and Equipment
4. Documentation
5. Production
6. Quality Control
7. Contract Manufacture and Analysis
8. Complaints and Product Recall
9. Self Inspection
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EU - GMP
Annexes
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

Manufacture of sterile medicinal products

Manufacture of biological medicinal products for human use
Manufacture of radiopharmaceuticals
Manufacture of veterinary medicinal products other than immunologicals
Manufacture of immunological veterinary medicinal products
Manufacture of medicinal gases
Manufacture of herbal medicinal products
Sampling of starting and packaging materials
Manufacture of liquids, creams and ointments
Manufacture of pressurised metered dose aerosol preparations for
inhalation
11. Computerised systems
12. Use of ionising radiation in the manufacture of medicinal products
13. Manufacture of investigational medicinal products
14. Manufacture of products derived from human blood or human plasma
Glossary

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Why
should
we
be
concerned?
Regulatory Inspections!
If a GMP violation is found,
Regulatory Agencies issue
observations for corrective
action

They can recommend

product recalls

They have the authority to

close a plant in the US, or
prevent product manufacture
in the UK.

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Approving process
Applications from pharmaceutical companies to the authorities
IND
NDA
ANDA
DMF

IND (Investigational New Drug) Clinical studies

NDA (New Drug Application) Launch of drug

ANDA (Abbreviated New Drug Application) generic drug
DMF (Drug Master File) manufacturing process

DMF approval process

PAI

GMP audit

PAI (Pre Approval Inspection), start up of manufacturing,

never approved only accepted (fulfilment of the GMP
guidelines)
GMP audit, running inspection, acceptance for
continued manufacturing (fulfilment of the GMP
guidelines)

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Pre-Approval Inspections
(from FDA)
PAIs are specific to the BLA, NDA or ANDA and challenge
the integrity and reproducibility of the specifications in the
BLA, NDA or ANDA.
Agency will also verify that the process is as described in the
DMF submitted to CDER (or CBER for a biologic). If the
data does not satisfy FDA, the investigator will send a
recommendation to CDER that the NDA approval be
withheld.
BLA=Biologics License Application
NDA=New Drug Application
ANDA=Abbreviated New Drug Application
DMF=Drug Master File
CDER=Center for Drug Evaluation and Research
Center for Biologics Evaluation
and
CBER=
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Regulatory Inspections
The regulator has the right
to inspect at his
discretion:

Buildings
Equipment
Production Records
Labelling & Packaging
Product Distribution
Raw Materials (and suppliers)

The regulator will inspect

when

New Facility or Process

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New Product
Complaint Profile Warrants
Periodically

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Examples from FDA guidance

Water systems

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Water systems
FDA Guideline - HIGH PURITY WATER SYSTEMS

A. Design/installation review
B. SOP development and confirmation
C. Demonstration of effectiveness
D. Data compilation and sign-off

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Validation strategy (Water systems)

A. Design/installation review:
A complete and up-to-date description and design
drawing of the system included in the final report
(including all components and clearly identify all
sample points and their designation) to ensure that
the validation is not put at risk and is successfully
completed

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Validation strategy (Water systems)

B. SOP development and confirmation
Develop the operational parameters and cleaning
and sanitising protocols. Collect data over a period
of two to four weeks, samples collected daily after
each purification step and from all point of use. If
successful, these procedures are established as
the water system's SOPs (Standard Operating
Procedure)

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Validation strategy (Water systems)

C.Demonstration of effectiveness
Demonstrate that the water system consistently
produces water of the desired quality when operated
within the parameters outlined in the SOPs over a
long period of time. WFI system samples are taken
daily at a minimum from one point of use and weekly
from all point of use. This identifies any inconsistence
in the feed water quality due to seasonal variations.
The water system can be considered validated after
the manufacturer has a years worth of operational
data.
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Validation strategy (Water systems)

D.Data compilation and sign-off
Assembly the data into a validation report including
all the data collected in steps B and C. Once
completed, ensure that the appropriate personnel
review and sign off are done.

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Validation
In the end, the test of any validation
process is whether scientific data
shows that the system consistently
does as expected and produces a
result that consistently meets
predetermined specifications

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FDA new paradigm initiatives

cGMP for the 21st Century: A Risk based Approach (2002)
Process Analytical Technology (PAT) for process control
through new technologies (2003)

The Critical Path to encourage innovation (2004)

The Critical Path

cGMP for the

21st Century

Process Analytical Technology

(PAT)

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Background Why new initiatives?

Industry Perspective:
Utilisation levels 15% or less
Scrap and rework plan for 5-10%
Time to effectiveness takes years
Hesitant to innovate
FDA Perspective
An increasing burden on FDA resources
Public Health Perspective
Increasing trend towards manufacturing related problems
Recalls 176 in 1998 rising to 354 in 2002

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Dr. Janet Woodcock, FDA Science Board

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cGMPs for the 21st Century

FDA is implementing a risk-based approach to regulating

pharmaceutical manufacturing

The approach will be applied to the review, compliance,

and inspectional components of FDA regulation

Industry encouraged to adopt Risk-based principles

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cGMPs for the 21st Century

Guiding Principles
Risk-based orientation
Science-based policies and standards
Integrated quality systems orientation
International cooperation
Strong Public Health Protection

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Commissioning and Qualification

activities
Today's practices

Focus on compliance, procedures and controls

The burden for Direct Impact systems is still big!

IQ, OQ etc. independent of the vendors capabilities

Protocols and reports just to check engineering
specs

Alfa Laval

Adopted from Iben E. Bechmann, NNE

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Commissioning and Qualification

activities
In the future - Product& Process Focus

Focus on critical processes and critical process

parameters

Project engineers determine acceptability of

equipment and systems from engineering point of
view

Qualification to ensure real quality and process

capability

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Adopted from Iben E. Bechmann, NNE

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PAT (Process Analytical Technology)

Regulatory approach:

1.

Improve the scientific basis for establishing

regulatory specifications

2.
3.

Promote continues improvement

Improve manufacturing while maintaining or
improving the current level of product quality

PAT Web page continues more information

http://www.fda.gov/cder/OPS/PAT.htm

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What is PAT in practice

Traditional Manufacturing without PAT:

Variable
process input

Fixed
process

Variable
process input

Robust &
Adjustable
process

Variable
process output

Manufacturing with PAT:

The key to PAT is using the
information gained to control and
manage processes, adjusting them
as needed to maintain the desired
state, resulting in more
consistency and quality

Consistent
process output

Ajaz Hussain, Deputy Director OPS, FDA

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Adopted from Iben E. Bechmann, NNE

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The Critical Path

Reducing Drug and Development Times
Reducing delays and cost in product approvals by avoiding multiple
review cycles
Improving the review process through a quality systems approach to
medical product review

Supporting Innovation in Medical Products

FDA can play a unique and critical role in facilitating the
advancement of technology by addressing and clarifying regulatory
uncertainty and by increasing predictability in product development
Cell and Gene Therapy
Pharmacogenomics/pharmacogenetics
Novel Drug Delivery Systems
Collaborative Clinical Guidance Development

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 Alfa Laval

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