Sunday, 31 March 2013

Validation Practices and Procedures

With the URS defined and the Validation Plan (VP) in deveopment Validation Risk Assessment VRA) must be authored and executed to establish the scope and depth of CNC validation that is appropriate for this equipment. This information must be published in the VP and used as the authority for all protocol development. Where vendor developed Functional Specifications FS) and or Design Specification (DS), are available they should be reviewed and referenced in the VP. Where these documents are not available a DS or FS may have to be retrospectively developed.
When the DS or FS that is to be used are defined, a pre-approved Design Qualification (DQ). The execution of this DQ must verify that the proposed design will;
Operate in a manner safe to the product, and the operations staff.
The installation of each validatable item and or system must be subjected to, and satisfy, a pre-approved Installation Qualification (IQ) protocol. Details of the scope of the IQ, responsibilities for generating, reviewing and approving of this document must all be documented in the VP.
When the requirements of the IQ have been satisfied, all aspects of the operational capabilities of each system must be fully challenged and verified by the execution of a pre-approved Operational Qualification(OQ) protocol. As with the IQ; OQ scope and details of the persons responsible for generating, reviewing and approving of this document will be documented in the VP.
As soon as the executed IQ and OQ protocols having been reviewed and approved, a pre-approved Performance Qualification (P1Q) protocol or Process Qualification P2Q) (this requirement will be documented in the VP) must be issued for execution.The execution of this PQ must verify that the system performance requirements, as specified in the URS have been achieved, and that the system operates in a manner safe to the product and production personnel.
1574443305 Pharmaceutical Master Validation Plan: The Ultimate Guide to FDA, GMP, and GLP Compliance
Syed Imtiaz Haider

Enhanced by Zemanta

cGMP Validation Scope

cGMP Validation requires the following procedures, processes and designs changes to be documented, approved and issued by Change Control . Once in use these procedures must be subjected to strict change control procedures and a rigorous system of routine and random audits that will produce documented evidence that these procedures are correct and are being applied in all aspects of cGMP compliance requirements. (21 CFR Part 820.70 relates). (21 CFR Part 211.100(a) relates).
Operators must receive sufficient training to enable them to proficiently and diligently work in accordance with these document procedures. (21 CFR Part 820.25(b) relates). (21 CFR Part 211.25(a) relates).
Documented directives and techniques must be written in clear and unequivocal language. Within the industry these instructions are referred to as Standard Operating Procedures or SOP?s. (21 CFR Part 70(1) relates). (21 CFR Part 211.)
Production records that record and therefore verify that all the specified manufacturing parameters; either manually observed or electronically recorded, have been complied with must be identified with all the relevant product identifications and securely retained. (21 CFR Part 820(2) relates) (21 CFR Part211.100(b) relates).
All deviations from these documented expectations that occur during product processing thoroughly investigated and the findings documented. (21 CFR Part 820.70 relates).
All records generated during manufacturing and distribution that are mandated as essential in establishing the entire manufacturing history of a product batch; to be traced, must be kept and retained in a secure, comprehensible and readily accessible form. (21 CFR Part 820.180(b) relates) (21 CFR Part 211.110(c) relates)
Product distribution, transit and storage conditions must ensure that the product efficacy, quality and records are never compromised. (21 CFR Part820.140 relates). (21 CFR Part 211.180(a) relates)
There must be a system in use that ensures all complaints about marketed products are promptly and diligently examined and the causes of quality defects investigated. (21 CFR Part 820.100(a) relates). (21 CFR Part 211.198(a) relates)
Where statistical analysis is used to verify the acceptability of a process capability, then there must be documented validation of the robustness and accuracy of this analysis procedure. (21 CFR Part 820.250(a) relates). (21 CFR Part 211.160(a) relates).
1574443305 Pharmaceutical Master Validation Plan: The Ultimate Guide to FDA, GMP, and GLP Compliance
Syed Imtiaz Haider

Enhanced by Zemanta

cGMP Validation Audit

AUDIT PREPARATION - For CGMP validation audit the Quality Auditor (team leader) must review all applicable change control records subsequent to a design transfer, any FDA clearance delay information, recall records, standard manufacturing procedures, device histories, complaint history, device labels and inserts, previous audits with results, follow-up audits, plus any other document relative to the audit.
AUDIT INITIATION - The Quality Auditor prepares/updates an audit checklist for systematic examination of the area to be audited, informs the Manager of the department being audited at the start of the audit, and reviews observations with the Department Manager.
AUDIT ANALYSIS - The Quality Auditor reviews the data gathered, verifies important details, and writes an audit report according to the format delineated in the attached audit report outline.
ISSUANCE OF AUDIT REPORT - The Quality Auditor issues the written audit report to the President and Department managers within three working days following completion of the audit. If conditions are critical, the Director of Quality Assurance shall verbally brief appropriate staff members within 12 hours following audit completion. Audit reports shall be stamped "Confidential".
CORRECTIVE ACTION - The appropriate Management staff member shall be responsible for developing a schedule for correcting deficiencies cited in the audit report and submitting same within five working days to the Quality Assurance Manager. Included in the correction schedule shall be the responsible individual, and the date when corrective action will be completed. The Manager of Quality Assurance shall act as arbiter, if necessary, to judge validity of the deficiency, responsible individual, and reasonable date to complete the corrective action.
B000Q7ZN0E GMP/ISO Quality Audit Manual for Healthcare Manufacturers and Their Suppliers, Sixth Edition - Volume 1 With Checklists and Software Package
Leonard Steinborn
Kindle Store: See all 3 items

093518466X Audit by Mail: Time and Cost Effective GMP Audit Tool
John Lyall

B003UHVRSO FDA Establishment Inspections: Pharmaceutical, Biotechnology, Medical Device and Food Manufacturing Concise Reference
Mindy J. Allport-Settle
Kindle Store: See all 3 items

B008JAOXLU ISO 13485 Lead Auditor Training
CALISO eLearning
Miscellaneous: See all 1 items

1574910752 GMP/ISO/EN Quality Audit Manual: For Healthcare Manufacturers and Their Suppliers, Fifth Edition, Software Package
Leonard Steinborn

0471738409 Establishing A CGMP Laboratory Audit System: A Practical Guide
David M. Bliesner

0849318467 GMP/ISO Quality Audit Manual for Healthcare Manufacturers and their Suppliers, Sixth Edition, (Volume 1 - With Checklis
Leonard Steinborn

1574910558 Quality and GMP Auditing: Clear and Simple
James L. Vesper

B0008IMIBI GMP audit leads FDA to IOL firm's monitoring.(Medical Development Research)(Brief Article): An article from: Bioresearch Monitoring Alert

B000PY458E Establishing A CGMP Laboratory Audit System: A Practical Guide
David M. Bliesner
Kindle Store: See all 3 items

AUDIT FOLLOW-UP - The Quality Auditor maintains a log listing deficiencies, responsible individual, target date for corrective action, and actual date of correction. If the same deficiency occurs on a second follow-up audit, the President shall be notified in writing by the Quality Assurance Manager.
LOG OF AUDITS AND FOLLOW-UP AUDITS - The master log shall be maintained by the Senior Quality Auditor. The audit log file shall include a copy of current audits, list of areas to be audited during the 12-month period, and list of areas audited to date (i.e., part of the Master Log).

Enhanced by Zemanta

Validation of Pharmaceutical Process Equipment1

1. Introduction
Validation, as it is known today, has developed from the need to maintain quality,
consistency, and above all,
public safety. Validation is a rapidly growing and evolving
subject. This evolution stems from technology’s astonishing growth rate, especially in
terms of what is available in computer hardware and software. Over the past 15 years,
machine automation
nd process control through the use of a computer has caused
additional concerns relating the validation of the processing system. Today, the computer
is used for everything from controlling the process, to automatically providing batch
reports, and providi
ng automated quality control.
The foundation of validation, the methodology behind validation, and the need for
validation will likely remain a key aspect of the industry we work in. This session reflects
the current industry trends and serves as an educ
ational tool in our progressive industry.
2. Definitions and Key Terms
These key terms are listed for your use in this session:
FDA definitions of Validation
“There shall be written procedures for production and process control designed to
assure that th
e drug products have the identity, strength, quality, and purity they
purport or are represented to possess.”
FDA Guideline “General Principles of Validation”, May 1987

“Establishing documented evidence which provides a high degree of assurance
that a spe
cific process will consistently produce a product meeting its pre
determined specifications and quality attributes.”
FDA Guideline “General Principles of Validation”, May 1987

The key idea is to provide a high level of documented evidence that the equipme
nt and the
process conform to a written standard. The level (or depth) is dictated by the
complexity of the system, process, or equipment. The validation “package” must
provide the necessary information and test procedures required to prove that the
em and the process meet the specified requirements.
“Installation Qualification”
Verification that the equipment/system is installed in a
proper manner and that all of the devices are placed in an environment suitable for
their intended operations.
“Operational Qualification”
Verification that the equipment performs as
expected throughout the intended range of use.
“Process Qualification”
Verification that the system is repeatable and
consistently producing a quality product.
A set of instructions that outline the organization of the Qualification
Documents. The protocol specifies the type of tests required and the order in which
the tests should be conducted.
3. Validation Life
Questions to consider:
What does vali
dation mean to the personnel in your company? What does validation
mean to your vendor?
Where does the responsibility lie for validation?
“FDA , End user, or Vendor?”
Process Validation vs. Equipment Validation vs. Validation Plan?
What is the differen
ce between the three?
Validation is a continuing and evolving process. The validation process extends from the
very basic specifics (how each item works and interacts with another item) to a very broad
theological and methodical investigation of how the s
ystem and processes perform. Its
scope encompasses documentation, revision control, training, and maintenance of the
system and process. Evidence of validation should be seen at the corporate level, and be
reflected in the management structure. Validatio
n is not just a set of procedures and rules
to satisfy FDA, validation is a method for building and maintaining
0849370558 Validation of Pharmaceutical Processes, 3rd Edition
James P. Agalloco

1574910795 Pharmaceutical Equipment Validation: The Ultimate Qualification Guidebook
Phillip A. Cloud

0824798872 Validation of Pharmaceutical Process Equipment

1439826609 Cleaning Validation Manual: A Comprehensive Guide for the Pharmaceutical and Biotechnology Industries
Syed Imtiaz Haider
When Does Validation Begin?
During the chemical development stage?
When you are currently developing a process?
When conducting clin
ical studies?
Ideally, validation starts in the very beginning, in the laboratory. In the lab, scientists
discover exactly how the product reacts, as well as the parameters that are required to
produce such a product. They learn under what conditions the p
roduct fails or becomes
unstable, unusable, and when its quality begins to suffer. Once the laboratory has
established the boundary processing criteria, this information can then be used for
establishing requirements for validation.
When Does Validation
After installation of the equipment?
After the initial validation?
After the first successful batch?
Validation of a system never truly ends. Once a new system and process have been
validated, the system still requires maintenance, periodic calibrat
ions and adjustment.
Therefore, the process [and consequently validation] is always under scrutiny and
constant evaluation. Session 2 will discuss when revalidation is required and how it fits
into a master validation protocol plan.
Shown on the follow p
age is a simplified flowchart of a validation life cycle. This flowchart
has been modified to show just one part of a project rather than the entire validation plan.
The first step involved in validating a new process is to formulate a good definition of
This means defining the following:
What the process is
Why is it needed
What will it be used for
How the elements of the system link together to perform the final process
Once the process has been completely defined, equipment usually will be requir
ed to
perform the actual processing of the product. This equipment will be collectively called
“The System”. The system and its operations can then be identified and defined.
Enhanced by Zemanta

Friday, 29 March 2013


There are two basic approaches to the validation of process itself (apart from the qualification of equipment used  in  production,  the  calibration  of  control  and
measurement  instruments,  the  evaluation  of environmental factors, etc). These are the experimental approach  and  the  approach  based  on  the  analysis  of historical  data.  The  experimental  approach,  which  is applicable  to  both  prospective  and  concurrent validation, may involve:
1.  extensive product testing,
2.  simulation process trials,
3.  challenge/worst case trials, and
4.  Control of process parameters (mostly physical)
One  of  the most  practical  forms  of  process  validation, mainly for non-sterile products, is the final testing of the product  to  the  extent  greater  than  that  required  in routine  quality  control.  It  may  involve  extensive sampling,  far  beyond  that  called  for  in  routine  quality control  and  specifications,  and  often  for  certain parameters  only.  Thus,  for  instance,  several  hundred tablets  per  batch  may  be  weighed  to  determine  unit dose uniformity. The results are then treated statistically to  verify  the  normality  of  the  distribution  and  to determine  the  standard  deviation  from  the  average weight.  Confidence  limits  for  individual  results  and  for batch homogeneity are also estimated. Strong assurance is  provided  that  samples  taken  at  random  will  meet regulatory  requirements  if  the  confidence  limits  are within compendia specifications.


The  key  idea  of  validation  is  to  provide  a  high  level  of  documented  evidence  that  the  equipment  and  the  process  conform  to  a  written  standard.  The  level  (or  depth)  is  dictated  by  the  complexity  of  the  system  or  equipment.  The  validation  package  must  provide  the  necessary  information  and  test  procedures  required  to  provide  that  the  system  and  process  meet  specified  requirements.  Validation  of  pharmaceutical  process  equipment involves the following :
1.  Installation Qualification: This ensures that all major  processing  and  packaging  equipment  and  ancillary  systems  are  in  conformity  with  installation  specification,  equipment  manuals  schematics  and
engineering  drawing.  It  verifies  that  the  equipment  has  been  installed  in  accordance  with
manufacturer’s  recommendation  in  a  proper manner  and  placed  in  an  environment  suitable  for
its intended purpose.
2.  Operational Qualification: This  is done  to provide a high  degree  of  assurance  that  the  equipment
functions  as  intended.  Operational  qualification should be conducted in two stages:
3.  Component  Operational  Qualification,  of  which calibration can be considered a large part.
4.  System  Operational  Qualification  to  determine  if the entire system operates as an integrated whole.
5.  Process Performance Qualification: This verifies that the  system  is  repeatable  and  is  consistently producing a quality product

These  exercises  assure,  through  appropriate  performance  lists  and  related  documentation,  that
equipment,  ancillary  systems  and  sub-systems  have  been  commissioned  correctly.  The  end  results  are  that all  future  operations  will  be  reliable  and  within prescribed  operational  limits.  At  various  stages  in  a validation  exercise  there  are  needs  for  protocols, documentation,  procedures,  specifications  and acceptance criteria for test results. All these need to be reviewed, checked and authorized. It would be expected that  representatives  from  the  professional  disciplines,
e.g.,  engineering,  research  and  development, manufacturing, quality control and quality assurance are
actively  involved  in  these  undertakings  with  the  final authorization  given by  a  validation  team or  the quality assurance representative


The concept of process validation from its beginnings in the  early  1970s  through  the  regulatory  aspects associated  with  current  good  manufacturing  practice (cGMP)  regulations  and  the  application  thereof  to various  analytical,  quality  assurance,  pilot  plant, production, and  sterile product and  solid dosage  forms considerations.  In  the  early  1990s,  the  concept  of preapproval inspection (PAI) was born and had as one of its  basic  tenets  the  assurance  that  approved  validation protocols and schedules were being generated and that comprehensive  development,  scale-up,  and  biobatch and  commercial batch  validation data were  required  in order to achieve a successful regulatory PAI audit. There are  several  important  reasons  for  validating  a  product and/or process.  First, manufacturers are required by law  to conform to cGMP regulations. Second, good business  dictates  that  a  manufacturer  avoids  the  possibility  of  rejected  or  recalled  batches.  Third,  validation  helps  to  ensure  product uniformity,  reproducibility,  and quality.  Although  the  original  focus  of  validation  was  directed  towards prescription drugs,  the FDA Modernization Act  of  1997  expanded  the  agency’s  authority  to  inspect  establishments  manufacturing  over-the-counter  (OTC)  drugs  to  ensure  compliance  with  cGMP.  Once  the  concept of being able to predict process performance to  meet  user  requirements  evolved,  FDA  regulatory  officials  established  that  there  was  a  legal  basis  for  requiring process validation. The ultimate legal authority
is  Section  501(a)(2)(B)  of  the  FD&C  Act,  which  states  that a drug  is deemed to be adulterated  if the methods  used  in,  or  the  facilities  or  controls  used  for,  its  manufacture,  processing,  packing,  or  holding  do  not  conform  to  or  were  not  operated  or  administrated  in  conformity  with  cGMP.  The  cGMP  regulations  for  finished  pharmaceuticals,  21  CFR  210  and  211,  were  promulgated  to  enforce  the  requirements  of  the  act.  FDA has  the authority and  responsibility  to  inspect and  evaluate  process  validation  performed  by  manufacturers.  The  cGMP  regulations  for  validating  pharmaceutical  (drug) manufacturing  require  that  drug  products be produced with  a high degree of  assurance  of  meeting  all  the  attributes  they  are  intended  to  possess



1.  Prospective  Process  Validation-  Where  an
experimental  plan  called  the  validation  protocol  is
executed  (following  completion  of  the  qualification
trials) before the process is put to commercial use. Most
validation  efforts  require  some  degree  of  prospective
experimentation in order to generate validation support
2.  Concurrent  Process  Validation-  Establishing
documented  evidence  that  the  process  is  in  a  state  of
control during the actual implementation of the process.
This  is  normally  performed  by  conducting  in-process
testing  and/or monitoring  of  critical  operations  during
the manufacture of each production batch.
3.  Retrospective  Process  Validation-  Where  historic
data  taken  from  the  records  of  the  completed
production  batches  are  used  to  provide  documented
evidence that the process has been in a state of control
prior to the request for such evidence[14,15]


The  principal  objective  of  dosage  form  design  is  to
achieve  a  predictable  therapeutic  response  to  a  drug
included in a formulation which is capable of large scale
manufacture  with  reproducible  product  quality.  To
ensure  product      quality,  numerous  features  are
required,  like  chemical  and  physical  stability,  suitable
preservation  against  microbial  contamination  if
appropriate, uniformity of dose of drug, acceptability to
users  including  prescriber  and  patient,  as  well  as
suitable packing, labeling, and validation[1]
The development of a drug product is a lengthy process
involving  drug  discovery,  laboratory  testing,  animal
studies,  clinical  trials  and  regulatory  registration.  To
further enhance the effectiveness and safety of the drug
product  after  approval, many  regulatory  agencies  such
as  the  United  States  Food  and  Drug  Administration
(USFDA) also require that the drug product be tested for
its identity, strength, quality, purity and stability  before
it  can  be  released  for  use.  For  this  reason,
pharmaceutical  validation  and  process  controls  are
important  in  spite  of  the  problems  that  may  be
The  concept  of  validation  was  first  proposed  by  two
Food and Drug Administration (FDA) officials, Ted Byers
and Bud  Loftus,  in  the mid  1970’s  in  order  to  improve
the  quality  of  pharmaceuticals.  The  first  validation
activities  were  focused  on  the  process  involved  in
making these products but quickly spread to associated
processes  involving  environmental  control,  media  fill,
equipment  sanitization  and  purified  water
In  a  guideline,  validation  is  act  of  demonstrating  and
documenting  that  any  procedure,  process,  and  activity
will consistently lead to the expected results. It  includes
the qualification of systems and equipment. The goal of
the  validation  is  to  ensure  that quality  is built  into  the
system at every step, and not just tested for at the end,
as  such  validation  activities  will  commonly  include
training  on  production  material  and  operating
procedures,  training of people  involved and monitoring
of the system whilst  in production.  In general, an entire
process  is  validated  and  a  particular  object within  that
process  is  verified.  The  regulations  also  set  out  an
expectation  that  the  different  parts  of  the  production
process  are well  defined  and  controlled,  such  that  the
results of  that production will  not  substantially  change
over time[5]

1.  It  would  not  be  feasible  to  use  the  equipments
without  knowing  whether  it  will  produce  the
product we wanted or not.
2.  The  pharmaceutical  industry  uses  expensive
materials,  sophisticated  facilities & equipments and
highly qualified personnel.
3.  The efficient use of  these resources  is necessary  for
the  continued  success  of  the  industry.  The  cost  of
product  failures,  rejects,  reworks,  and  recalls,
complaints  are  the  significant  parts  of  the  total
production cost.
4.  Detailed  study  and  control  of  the  manufacturing
process-  validation  is  necessary  if  failure  to  be
reduced and productivity improved.
5.  The pharmaceutical  industries  are  concerned  about
validation because of the following reasons.
6.  Assurance of quality.
7.  Cost reduction.
8.  Government regulation[6,7]
1.  Site validation committee (SVC): Develop site master
validation  plan,  Prepare/  execute/  approve
validation studies.
2.  Manufacturing department: Prepares the batches as
a routine production batch.
3.  Quality  assurance:  Ensure  compliance,  see  that
documentations/ procedures are  in place, approves
protocols and reports.
4.  Quality  control:  Perform  testing  and  reviews
protocol and report as needed[7]

  The  validation  working  party  is  convened  to  define
progress, coordinate and ultimately, approve  the entire
effort,  including  all  of  the  documentation  generated.
The working  party would  usually  include  the  following

staff members, preferably those with a good insight into
the company’s operation.
•  Head of quality assurance.
•  Head of engineering.
•  Validation manager.
•  Production manager.
•  Specialist validation discipline: all areas
Department /Designation  Responsibility
Manager Production  Responsible for manufacturing of batches and review of
protocol and report.
Manager QC  Responsible   for   analysis   of   samples
Executive QC  Responsible for samples collection and
submission to QC
Manager Maintenance  Providing     utilities     and     engineering
Executive Production  Responsible for preparation of protocol and manufacturing of
validation batches
Manager QA  Responsible   for   protocol   authorization and preparation of
summary report.
Validation  is  an  integral  part  of  quality  assurance;  it
involves  the  systematic  study  of  systems,  facilities  and
processes  aimed  at determining whether  they perform
their  intended  functions adequately and consistently as
specified.  A  validated  process  is  one  which  has  been
demonstrated  to  provide  a  high  degree  of  assurance
that  uniform  batches  will  be  produced  that  meet  the
required specifications and has therefore been formally
approved.  Validation  in  itself  does  not  improve
processes  but  confirms  that  the  processes  have  been
properly  developed  and  are  under  control.  Adequate
validation  is  beneficial  to  the  manufacturer  in  many
1.  It  deepens  the  understanding  of  processes;
decreases  the  risk of preventing problems and  thus
2.  The smooth running of the process.
3.  It decreases the risk of defect costs.
4.  It decreases the risk of regulatory noncompliance.
5.  A fully validated process may require  less  in-process
controls and end product testing[8,9]

Design Qualification (DQ):-
It  is  a  documented  review  of  the  design,  at  an
appropriate  stage  of  stages  in  the  project,  for
conformance  to  operational  and  regulator
DQ check items:
1.  Goods  manufacturing  practices  and  regulator
2.  Performance criteria.
3.  Facility  air  flow,  movement  flow  and  pressur
4.  Reliability and efficiency.
5.  Commissioning requirements.
6.  Construct ability and installation of equipment.
7.  Maintenance  and  access  to  critical  equipment  an
8.  Safety and environment impact.

It  is a documented verification  that all  the aspects of
facility,  utility  or  equipment  that  can  affect  produc
quality  adhere  to  approved  specifications  and  ar
correctly installed.
Important IQ considerations are:
1.  Installation  conditions  (wiring,  utilities  an
2.  Calibration,  preventive  maintenance,  cleanin
3.  Safety features.
4.  Supplier  documentation,  prints,  drawings  and
5.  Software documentation.
6.  Spare parts list.
7.  Environmental  conditions  (such  as  clean  room
requirements, temperature and humidity).
8.  Equipment  design  features  (i.e.  materials  of
construction clean ability).

It  is  a  documented  verification  that  all  aspects  of  a
facility,  utility  or  equipment  that  can  affect  product
quality  operate  to  intend  throughout  all  anticipated
OQ considerations include:
1.  Process  control  limits  (time,  temperature, pressure,
line speed and set up conditions).
2.  Software parameters.
3.  Raw material specifications.
4.   Process operating procedures.
5.  Material handling requirements.
6.  Process change control.
7.  Training.
8.  Short  term  stability  and  capability  of  the  process
(latitude studies or control charts).
9.  Potential failure modes, action levels and worst-case
conditions (Failure Mode and effects).
10. Fault tree analysis.

It  is  a  documented  verification  that  all  aspects  of  a
facility,  utility  or  equipment  perform  as  intended  in
meeting predetermined acceptance criteria.
PQ considerations include:
1.  Actual  product  and  process  parameters  and
procedures established in OQ.
2.  Acceptability of the product.
3.  Assurance of process capability as established in OQ.
4.  Process repeatability, long term process stability
Major Phases in Validation
The  activities  relating  to  validation  studies  may  be
classified into three:
Phase  1:  This  is  the  Pre-validation  Qualification  Phase
which  covers  all  activities  relating  to  product  research
and development, formulation pilot batch studies, scale-
up  studies,  transfer  of  technology  to  commercial  scale
batches,  establishing  stability  conditions  and  storage,
and  handling  of  in-process  and  finished  dosage  forms,
equipment  qualification,  installation  qualification,
master  production  document,  operational  qualification
and process capacity.
Phase  2:  This  is  the  Process  Validation  Phase.  It  is
designed  to  verify  that  all  established  limits  of  the
critical process parameter are valid and that satisfactory
products  can  be  produced  even  under  the  worst
Phase 3: Known as the Validation Maintenance Phase, it
requires  frequent  review  of  all  process  related
documents,  including  validation  of  audit  reports,  to
assure  that  there  have  been  no  changes,  deviations,
failures and modifications to the production process and
that all standard operating procedures (SOPs),  including
change control procedures, have been followed. At  this
stage,  the  validation  team  comprising  of  individuals
representing  all  major  departments  also  assures  that
there  have  been  no  changes/deviations  that  should
have  resulted  in  requalification  and  revalidation[11]
.  A
careful  design  and  validation  of  systems  and  process
controls can establish a high degree of confidence  that
all  lots  or  batches  produced  will  meet  their  intended
specifications.  It  is  assumed  that  throughout
manufacturing and control, operations are conducted in
accordance  with  the  principle  of  good  manufacturing
practice (GMP) both in general and in specific reference
to  sterile  product  manufacture.  The  validation  steps
recommended in GMP guidelines can be summarized as
1.  As a pre-requisite, all studies should be conducted in
accordance with a detailed, pre-established protocol
or  series  of  protocols,  which  in  turn  is  subject  to
formal – change control procedures;
2.  Both the personnel conducting the studies and those
running  the  process  being  studied  should  be
appropriately  trained  and qualified  and be  suitable
and  competent  to  perform  the  task  assigned  to

3.  All  data  generated  during  the  course  of  studies
should  be  formally  reviewed  and  certified  as
evaluated against pre-determined criteria;
4.  Suitable  testing  facilities,  equipment,  instruments
and methodology should be available;
5.  Suitable  clean  room  facilities  should be  available  in
both the ‘local’ and background environment. There
should  be  assurance  that  the  clean  room
environment  as  specified  is  secured  through  initial
commissioning  (qualification)  and  subsequently
through  the  implementation of a programme of  re-
testing  –  in-process  equipment  should  be  properly
installed, qualified and maintained;
6.  When  appropriate  attention  has  been  paid  to  the
above,  the  process,  if  aseptic, may  be  validated  by
means of “process simulation” studies;
7.  The process should be revalidated at intervals; and
8.  Comprehensive  documentation  should  be  available
to  define  support  and  record  the  overall  validation

Protocols should specify the following in detail:
1.  The  objective  and  scope  of  study-  There  should
already be a definition of purpose;
2.  A clear and precise definition of process equipment
system  or  subsystem, which  is  to be  the  subject  of
study with details of performance characteristics;
3.  Installation  and  qualification  requirement  for  new
4.  Any  upgrading  requirement  for  existing  equipment
with justification for the change(s) and statement of
qualification requirement;
5.  Detailed  stepwise  statement of  actions  to be  taken
in performing the study (or studies);
6.  Assignment  of  responsibility  for  performing  the
7.  Statement on all  test methodology  to be employed
with  a  precise  statement  of  the  test  equipment
and/or materials to be used;
8.  Test equipment calibration requirements;
9.  References  to  any  relevant  standard  operating
procedures (SOP);
10. Requirement for the current format of the report on
the study;
11. Acceptance  criteria  against  which  the  success  (or
otherwise) of the study is to be evaluated; and
12. The  personnel  responsible  for  evaluating  and
certifying the acceptability of each stage in the study
and  for  the  final  evaluation  and  certification of  the
process  as  a  whole,  as  measured  against  the  pre-
defined criteria[12]
13. All  personnel  involved  in  conducting  the  studies
should  be  properly  trained  and  qualified  because
they  can,  and  often,  have  a  crucial  effect  on  the
quality  of  the  end  product.  All  information  or  data
generated as a result of the study protocol should be
evaluated  by  qualified  individuals  against  protocol
criteria  and  judged  as  meeting  or  failing  the
requirements.  Written  evidence  supporting  the
evaluation  and  conclusion  should  be  available.  If
such an evaluation shows that protocol criteria have
not  been  met,  the  study  should  be  considered  as
having  failed  to  demonstrate  acceptability  and  the
reasons  should  be  investigated  and  documented.
Any  failure  to  follow  the procedure as  laid down  in
the  protocol  must  be  considered  as  potentially
compromising  the  validity  of  the  study  itself  and
requires  critical  evaluation  of  all  the  impact  on  the
study.  The  final  certification of  the  validation  study
should  specify  the  pre-determined  acceptance
criteria  against  which  success  or  failure  was

Process  validation  is  defined  as  the  collection  and
evaluation  of  data,  from  the  process  design  stage
throughout  production,  which  establishes  scientific
evidence  that  a  process  is  capable  of  consistently
delivering  quality  products.  Process  validation  is  a
requirement  of  current  Good  Manufacturing  Practices
(GMPs) for finished pharmaceuticals (21 CFR 211) and of
the  GMP  regulations  for medical  devices  (21  CFR  820)
and  therefore applies  to  the manufacture of both drug
products  and  medical  devices.  Process  validation
involves  a  series  of  activities  taking  place  over  the
lifecycle of the product and process