validation. chemical and biological evaluation, cleaning validation, personal validation,technology transfer

1. Validation
Submitted by:
Sharath . H . N
M.Pharma
Submitted to :
Mr.Manish Majumder,
Associate professor
Dept. of pharmaceutical
analysis

2. Index
• Introduction & scopes of Validation
• Cleaning validation
• Personal validation
• Technology transfer

3. VALIDATION

4. Introduction
Validation is " a process of establishing documentary
evidence demonstrating that a procedure, process, or
activity carried out in production or testing maintains the
desired level of compliance at all stages.
Here the desired results are established in terms of
specifications for out come of the process. Qualification of
systems and equipment is therefore a part of process of
validation. It is a requirement of food and drug,
pharmaceutical regulating agencies like FDA's good
manufacturing practices guidelines.

5. Since a wide variety of procedures, processes, and activities
need to be validated, the field of validation is divided into a
number of subsections including the following:
>Equipment validation
>Facilities validation
>HVAC system validation.
>Cleaning validation
>Process Validation.
>Analytical method validation
>Computer system validation
>Packaging validation

6. Similarly, the activity of qualifying systems and
equipment is divided into a number of
subsections including the following:
Design qualification (DQ)
Component qualification (CQ)
Installation qualification (IQ)
Operational qualification (OQ)
Performance qualification (PQ)

7. Scope of validation
1 There should be an appropriate and sufficient system including
organizational structure
and documentation infrastructure, sufficient personnel and financial
resources to perform
validation tasks in timely manner. Management and persons responsible
for Quality Assurance
should be involved.
2 Personnel with appropriate qualifications and experience should be
responsible for
performing validation. They should represent different departments
depending on the
validation work to be performed.
3 There should be proper preparation and planning before validation is
performed. There
should be a specific programme for validation activities.

8. 4 Validation should be performed in a structured way according to the
documented
procedures and protocols.
5 Validation should be performed for (1) new premises, equipment, utilities and
systems,
and processes and procedures, (2) at periodic intervals, and (3) when major
changes have been
made.
6 Validation should be performed in accordance with written protocols. The
outcome of
the validation should be reflected in written reports.
7 Validation can be prospective, concurrent, or retrospective, depending on
when
validation is performed.
8 Validation should be done over a period of time, e.g. at least three
consecutive batches
(full production scale) should be validated, to show consistency. Worst case
situations should
be considered.

9. Cleaning validation
Cleaning validation in the pharmaceutical industry has been a topic of
ever-increasing interest and scrutiny in recent Food and Drug
Administration (FDA) inspections.
The validation of procedures used to
clean the equipment employed during the various steps of a manufacturing
process is a clear requirement of current Good Manufacturing Practice
(cGMP).

10. Definition
Cleaning validation may be defined as " a process of
attaining & documenting sufficient evidence to give
reasonable assurance , given the current state of
science & technology, that the cleaning process under
consideration does, andor will do ,what it purports to
do".

11. Objectives

12. It is necessary to Validate Cleaning procedures for
the following reasons:
• Pharmaceutical products and API can be contaminated by
other pharmaceutical products, cleaning agent & microbial
contamination.
• It is regulatory requirement in pharmaceutical product
manufacture the concern is the same-assurance that
equipment is clean and that product quality and safety are
maintained.
• It is also assure from an internal control and compliance
point of view the quality of manufacture.
• To protect product integrity To reuse the equipment

13. Other objectives
• Solvent reduction,
• Shorter cleaning times,
• increased equipment- Utilization,
• extension of equipment life,
• multiproduct- Facilities,
• worker safety, and cost- eff

14. Various steps involved
- Visual inspection
-Rinse water sampling and
analysis
-Surface sampling & analysis
-Method selection
-Solvents
-Sampling methods
-Residue detection
-Analytical Evaluation
-Worst- case determination
- Acceptance criteria

15. Visual inspection
✓ Active product contact parts of the equipment are individually examined
(wherever possible) for cleanliness. This visual inspection allows the early
localization and identification of any inadequacies in the cleaning
procedure.
✓ Qualitative – dependent upon inspection and item sampled.
• Rinse water sampling and analysis
✓ Analysis can be quantitative, using pH, conductivity, particle
count,microbial count, Total Organic Carbon (TOC) determination,
spectrophotometry, bioassays or limulus amebocyte lysate for pyrogens.
✓ Recovery factor is uncertain; it involves dilution

16. .
Surface sampling from coupons
✓ Quantitative.
✓ Depends on whether coupons are equivalent to the surface of
interest.
✓ Requires removing coupons from the system.
• Method Selection
Whenever possible, each piece of equipment should be dismantled
into its individual components after cleaning and each part should
be individually tested for cleanliness. In this manner, any
inadequacy in the cleaning process will be more readily identified
and localized.

17. Solvents
Aqueous or organic solvents used in the cleaning procedure,
should be sufficient to remove residues, and at the same time,
should be minimized to reduce the risk of reaction with or damage
to the equipment, or the over-dilution of the residue and the result-ant l
of analytical sensitivity.
Samples should be collected in clean or sterile containthis

18. • Sampling Methods
The sampling method selection for cleaners, involves choosing
between rinse water sampling, swabbing surfaces, coupon
sampling, or placebo sampling. Rinse water sampling involves taking
a sample of an equilibrated post-final rinse that has been re-
circulated over all surfaces. Rinse samples should be correlated to a
direct measuring technique such as swabbing.

19. Residue Detection
Selecting a method to detect cleaner residues can involve specific
methods for specific cleaner ingredients such as: HPLC), ion selective
electrodes, flame photometry, derivative UltraViolet (UV)
spectroscopy, Thin Layer Chromatography, enzymatic detection, and
titration. It can also involve non-specific methods that detect the
presence of a blend ofingredients such as: TOC, pH, and conductivity.
Analytical Evaluation
Analytical validation of the cleaning procedure should be performed
after the approval of visual inspection (absence of stains or any
materiel residue). The specificity, sensitivity, and percentage of
recovery of the test method should be adequate to meet acceptance
criteria.

20. • Worst-Case Determination
Worst-case determination of cleaning validation is a crucial step in defining
contamination limits and in cleaning procedure efficacy. A worst-case
determination study should be based on: active product
solubility; active product toxicity; smallest batch size that can be manufactured
using the equipment concerned; the maximum daily dose of this product.
➤ Acceptance Criteria
In determining the final acceptance criteria for a cleaning validation exercise, the
calculation of the acceptable level of contaminant in the next product maximum
therapeutic patient dose is of primary importance. Acceptance criteria are
established by considering the contaminant type, the facility, and the risk to the
operator, product, and patient.

21. Cleaning Analytical Method Validation
The following sections should be included:
➤ Scope
•Describe the active product (s) that could be evaluated by the method.
•Describe the method followed to determine the acceptance criteria the
The major and critical acceptance criteria to be mentioned are as follows:
active product recovery percentage and active percentage
(contaminant) µg per cm2 or µg of active residual (contaminant)
per maximum daily dose units of next product.
➤ Method
Description of analytical methods used: standard preparation, sample preparation,
analytical equipment used, analytical parameters, equipment parameter, sample volume
materials used, and the determination of the following values (which are specific to the
analytical method and are relative for each active product):

22. • Precision
• Accuracy
• Limit of Detection
• Limit of Quantitation (LoQ)
• Linearity (where appropriate, linearity of
detector response for standard solution over a
range of concentrations)
• Recovery percentage
• Absence of interference between swab materials
and active product
• Absence of interference between solvent and
active product

24. Personal validation

25. PERSONAL VALIDATION
The basic purpose of personal validation is evaluate and measure
the work behavior, quality of work, job knowledge with a focus on
the accuracy in the assigned work by analyzing the work
characteristics, effective communication & positive relationship
that a personnel display at work place.
SCOPE
The Personnel Validation covers all aspects of GMP which
includes performance dimension

26. The regulatory guidelines talks about many things, about
people.some of these are as follows:
1.people must be qualified,experienced & trained.
2. They must be sufficient in number.
3. Their job responsibilities must be well explained to
them & monitered.
4. They must be highly motivated.

27. 1.Qualification,Experience & Training
(a). Qualifications:
W.H.O giidelines on GMP give some guidelines on the
qualifications
For eg: the education should include study of an
appropriate combination of chemistry( analytical & organic)
or biochemistry, chemical engineering, microbiology,
PST,pharmacology & toxicology& other related sciences.

28. (b) Training of Employees:
A person is called " a trained person ", when he has appropriate
knowledge, skill and attitude.
(c) Sufficient number of people:
According to guidelines there should be sufficient number of
people to carry out the tasks which manufactures are responsible".
(d) Ability to perform given task at given level:
Peoples are trained to perform different levels of operations to
perform the designated jobs.
(e) Appropriate managerial skills:
Managerial skills carryout functions of planning, organising ,
staffing, leading & controlling.

29. 2.Responsibilities & key personnel
(a). Responsibilities & Job description:
In a pharmaceutical plant different jobs are performed, so it be comes
important to have clarity & specification over his job.
(b). Key personnel:
Key personals are position in the organisation,which have a direct
impact on the working organisation & quality of products produced.
For eg:
-The head of Quality control
-The head of production.
-Joint responsibities of Q.C.
& production heads.

30. 3.Personal hygiene & clothing
According to guidelines , we need to maintain high level of hygienic
conditions in manufacturing environment.
Few of guidelines mentioned below:
-High standards of personal cleanliness should be maintained,
stringent rules followed for manufacturing of sterile products.
-Habit of hand washing must be inculcated in all the employees.
-Eating, drinking, smoking, storage of food should not be allowed
within manufacturing areas.

31. -Direct contact of operator hands with any part of equipment
should be avoided.
-Visual inspection staff should pass an annual eye inspection.
-Only personal authorised by supervisory personal shall enter
those areas of buildings & facilities.

32. LEGAL ASPECTS
Personal related legal aspects are covered in regulatory
literature,only by M.C.C ,south africa guidelines,W.H.O &
schedule M of D & C act of India.
1.Schedule M of D & C act India:
It says manufacturing should be done in supervision of
competent technical staff with prescribed qualifications
W.H.O guidelines:
It says that key personnel responsible for supervising the
manufacture & QC of pharmaceutical products should possess
the qualification of a scientific education & practical experience
required by national legislation.

33. 3.M.C.C. South africa:
It says that
- The company & MD must register in pharmacy council.
-Pharmaceutical operations must be conducted under supervision of
pharmacists displayed over main entrance.
- Duties like compounding, manufacturing, distribution & sale of
medicines must be performed by pharmacists.

34. - Other legal requirementslike, labellings & packaging of
medicines,maintaining records & registers, reporting errors,
advertising can be carried out..
Documents required:
-Copies of drug licenses given by drug control authorities along
with list of products permitted to be manufactured.
-list of competent technical staff along with their copy of
certificate of approval.

35. 5.CONSULTANTS.
Consultant is a person who provides expert advice
professionly.Regulatory authorities allow, pharmaceutical
manufacturer to seek such advice from consultents.
(a). As per U.S.F.D.A
1. It has identified certain ares for such advice
eg.manufacture, processing, packaging & holding of products.
2.Such consultants must have sufficient educatiom,traimg &
experiance or any combination.
3.Manufacture should maintain records of such consultants giving
the following details:
-Name,Address,Qualifications, Types of service provided.

36. (b). M.C.C South africa
- only in exceptional circumstances should persons be
engaged part time or in a consultative capacity be
appointef to key positions.
- Other datails remain same as given by U.S.F.D.A.
Documents required
-Records of consultants, giving details of name,
qualifications,address & type of consultancu provided.

37. Technology
transfer

38. Introduction
Transfer of processes to an alternative site occurs at some stage in the life-cycle of
most products, from development, scale-up, manufacturing, production and launch,
to the post-approval phase.
Transfer of technology is defined as “a logical procedure that controls the transfer
of any process together with its documentation and professional
expertise between development and manufacture or between manufacture sites”. It
is a systematic procedure that is followed in order to pass the documented
knowledge and experience gained during development and or commercialization to
an appropriate, responsible and authorized party.
Technology transfer embodies both the transfer of documentation and the
demonstrated ability of the receiving unit (RU) to effectively perform the critical
elements of the transferred technology, to the satisfaction of all parties and any
applicable regulatory bodies.

39. 1 This document gives guidance in principle and provides general recommendations on
the activities necessary to conduct a successful intra-or intersite transfer of technology as
described in the Introduction to these guidelines. The intention is to address the basic
considerations needed for a successful transfer in order to satisfy the regulatory
authority defined for the transfer pradvice
2 The guidelines will be applied to manufacturing active pharmaceutical ingredients
(APIs), manufacturing and packaging of bulk materials, manufacturing and packaging of
finished pharmaceutical products (FPPs) and performing analytical testing.
3 The recommendations provided in these guidelines apply to all dosage forms but need
to be adjusted on a case-by-case basis (e.g. by using risk management principles).
Particularly close control of certain aspects will be required for certain formulations such
as sterile products, and metered-dose aerosols. WHO guidance on manufacture of
specific pharmaceutical products will be useful in this regard.
Scope

40. The guidelines address the following areas at the SU and the RU:- transfer of
development and production (processing, packaging and cleaning);
— transfer of analytical methods for quality assurance and quality control;
— skills assessment and training
— organization and management of the transfer
— assessment of premises and equipment
— documentation and
— qualification and validation.

43. Production: transfer (processing, packaging circumstances
1 The RU should be able to accommodate the intended production capacity. If
possible, it should be established at the outset whether the intention is to
perform single-batch manufacture, continuous production or campaigns.
2 Consideration should be given to the level and depth of detail to be transferred
to support production and any further process development and optimization at
the RU as intended under the transfer project plan.
3 Consideration should be given to the technical expertise, site technology and
site capabilities for the RU. It should be identified upfront by the SU of any
process robustness issues so that plans may be put in place at the RU.
4 The SU and the RU should jointly develop a protocol for the transfer of relevant
information related to the process under consideration from the SU to the RU, as
well as the development of a comparable process at the RU.

45. Premises and equipment
Premises
1 The SU should provide information to the RU on the layout, construction and finish of
buildings and services (heating, ventilation and air-conditioning (HVAC), temperature,
relative humidity, water, power, and compressed air), which have an impact on the product,
process or method to be transferred.
2 The SU should provide information on relevant health, safety and eenvironmental issues,
including:
• inherent risks of the manufacturing processes (e.g. reactive chemical hazards, exposure
limits, fi re and explosion risks);
• health and safety requirements to minimize operator exposure (e.g. atmospheric
containment of pharmaceutical dust);
• emergency planning considerations (e.g. in case of gas or dust release, spillage, fi re and
firewater run-off); and
• identification of waste streams and provisions for re-use, recyclingorr disposal.

46. Equipment
3 The SU should provide a list of equipment, makes and models
involved in the manufacture, filling, packing and control of the
product, process or method to be transferred, together with existing
qualification and validation documentation.

47. Documentation
1 The documentation required for the transfer project itself is wide-ranging.
2 The documented evidence that the transfer of technology has been considered
successful should be formalized and stated in a technology transfer summary
report. That report should summarize the scope of the transfer, the critical
parameters as obtained in the SU and RU (preferably in a tabulated format) and the
final conclusions of the transfer. Possible discrepancies should be listed and
appropriate actions, where needed, taken to resolve it.

48. Qualification and validation
General
.1 The extent of qualification and or validation to be performed should be
determined on the basis of risk management principles.
Qualification and validation should be documented.

49. References :
1.Analytical method development and validation by michel E
Swartz
2.Pharmaceutical Quality Assurance by Manohar.A.Potdar
2.ICH 10 Pharmaceutical quality system.
3.Good manufacturing guidelines.
4.Validation Wikipedia.
5.Internet source.

50. Thank you
Questions;
Answers: