مجلة العراق الدوائية: Validation Requirements in Common Technical Document

Validation Requirements in Common Technical Document

من مواضيع نشرة الاتحاد العربي
Bashar Faidi
Pharma international Co

Process
- Concept
- Development
* Validation
* Process validation
* When PV is required
* Interaction of PV with other validation activities
* Regulatory basis (Examples)
* Validation activities structure
* Regulatory submission
* Comparison between pre-approval & post-approval
batch manufacturing.
* A new concept of process validation.
* Method validation
* Recommendations

Process
The horizontal look "Part of a system”

* Materials: API, Excipients, Container/ Closure, Purified Water/ WFI,
* Materials: API, Excipients, Container/ Closure, Purified Water/ WFI, Compressed air, Filters, Steam and Cleaning/ Disinfection materials.
4M's
* Manpower: Experience and training.
* Machines: Design, Capacity, Operation, Cleaning, Utilities, and Control system.
* Media: Air quality, Light, Temp. and Humidity

Process
The vertical look "Hierarchy"

Example: Manufacturing process of Paracetamol tablets by WG technique

1. Procedures: cleaning of equipment, weighing of materials, writing in batch
record, sampling, testing of moisture in tablets, …etc
2. Unit operations: wet granulation, drying, blending, compression, …etc.
3. Process: All of the above.

Validation
The planned activities organized to assure that procedures, materials,equipment, systems or processes lead to the expected results.
Validation is a mix of science and art which investigates all the possible causes that lead to the effect (Cause - effect
relationship)

The FDA defines process validation as follow: process
validation is 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
characteristics.

When Process Validation is Required?

1. Manufacturing of sterile products (LVP, SVP, Ophthalmic,
…etc)
2. Manufacturing of new product
3. Critical change in existing manufacturing process:
- Change in composition (addition or deletion of a
component or change beyond SUPAC levels)
- Change in equipment.
- Change in method of manufacturing.
- Change in batch size
- Change in manufacturing site.
4. Inconsistent process or frequent process failure.
5. Required by health authorities for submission or
inspection purposes.
6. Product quality problems like recalls, frequent
complaints, stability problems, …etc.

Interaction of PV With
Other Validation Activities

*Equipment qualifications (IQ/ OQ)
*Materials qualifications (API, filler,
Lubricant,
Disintegrant).
*Analytical method validation (assay,
related substances
and dissolution/ release).
*Water treatment system validation
(particularity if purified water is
involved in the manufacturing
Process).
*Support system validation
(compressed air, PLCs,
Steam).
*HVAC qualifications (Temp.,
Humidity, Particulate
Contamination).

Regulatory basis
*Validation is an integral part of
cGMP which is concerned by
industry and health authorities
*Part of requirements for submission
and inspection,validation activities,
reports and protocols that are
Eviewed by authorities to assure
control over process,system and
procedures that affect product quality
*Some health authorities ask for a lot
of validation (like in EU) at
submission stage and others (as in
US)
submission stage and others (as in
US)
concentrates on validation issues at
inspection on manufacturing site
before giving final approval
*When reviewing rules and
guidances, the validation is required
by general terms (indirectly) or by
Specific terms (directly).
Examples

Current GMP regulations for finished pharmaceuticals, 21
CFR parts 210 and 211
Example 1:
A requirement for process validation is set forth in general terms in section
211.100- written procedures; deviations - which states, in part:
"There shall be written procedures for production and process control
designed to assure that the drug products have the identity, strength,
quality, and purity they purport or are represented to possess".

Example 2:
Several sections of the CGMP regulations state validation requirements in more specific terms. From some of these sections are:

Section 211.110, sampling and testing of in process materials and drug products.
"Control procedures shall be established to monitor the output and validate the performance of those manufacturing processes
that may be responsible for causing variability in the characteristics of in-process material and the drug product".

Section 211.113, control of microbiological contamination
"Appropriate written procedures, designed to prevent
microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process".

A new concept of process validation
(FDA Guidance for industry, Process validation: General
Principles and practices.
November/2008)
* Product lifecycle concept:
The concept links product and process
development, qualification of the
commercial manufacturing process,
and maintenance of the process in a
state of control during routine commercial production.

Stages of process validation (by product lifecycle concept)
1. Process design : The goal of this
stage is to design a process suitable
for routine commerical manufacturing
that can consistently deliver a product that meets its critical quality
attributes.
1.a. Building & capturing process knowledge and understanding.
1.b. Establishing a strategy for process control.
2. Process qualification The goal of this stage is to confirm that the
process design is being capable of
achieving reproducible commercial manufacture.
2.a. Design of afacility and qualification of utilities and equipment.
2.b. Performance qualification approach
2.c. Performance qualification protocol.
2.d. Protocol execution and report.

3. Continued process verfication.
The purpose is to continaually assure that the process remains in a state of control during commercial manufacture
*N.B: If biobatch is needed to be
Manufactured, it should be under GMP conditions
Method Validation
* Critical methods that affect product
quality, safety and efficacy:
1. Assay methods:
a. Stability indicating method (for
stability studies and release purposes).
b. Routine methods (for blending
homogeniety and process control)

2. Related substances method (for
stability studies, release purposes,
purity, …etc)
3. Dissolution/ release method (for
product development, Q.C release, in
vitro profiling, …etc).
* Method transfer: between method
development lab. and application lab.

Recommendations
* There should be a consensus of
what level of validation is required at preapproval and post approval stages.
* The content of process validation
activities should be defined when
Required to be submitted to regulatory authorities.