Monday, November 29, 2010

Process Validation

Process Validation for solid dosage forms:
Process validation establishes the flexibility and constraints in the manufacturing process controls in the attainment of desirable attributes in the drug product while preventing undesirable properties. This is an important concept, since it serves to support the underlying definition of validation, which is a systematic approach to identifying, measuring, evaluating, documenting, and re-evaluating a series of critical steps in the manufacturing process that require control to ensure a reproducible final product.
USFDA defined process validation as “establishing documented evidence which provides high degree of assurance that a specific process will consistently produce a product meeting its pre determined specifications and quality characteristics.
Despite the ongoing development of more sophisticated solid drug delivery systems, tablets are still by far the most prevalent solid dosage form.  The emphasis will be on the practical inspectional requirement, rather than on a theoretical approach that does not reflect the practicalities (and problems) encountered when validating actual production operations.
TYPES OF PROCESS VALIDATION:
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 data.
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.
GUIDELINES FOR PROCESS VALIDATION OF SOLID DOSAGE FORMS:
Numerous factors should be considered when developing and validating solid dosage forms. As a means of providing a broad overview of these validation criteria, the following checklist/guideline as in Table 1, is provided for tablets and dry-filled capsules for inclusion in an in-depth validation program. Some of these unit operations will not be applicable for every solid dosage form (e.g., direct compression tablets and uncoated tablets).
Table 1: Check list of Validation and Control Documentation
Sr. No.
Selection of cGMP
Validation and control documentation
1
Introduction
Establishing of QA & PV functions
2
Organization and personnel.
Establishment and facility installation and qualification
3
Buildings and facilities
Plant and facility installation qualification
Maintenance and sanitation
Microbial and pest control
4
Equipment
Installation and qualification cleaning methods.
5
Air and water quality
Water treatment and steam systems air, heat, and vacuum handling.

6
Control of raw material, in-process material, product
Incoming components 
Manufacturing non-sterile products 

7
Production and process controls
Process control systems (instruments and computers)
8
Packing and labeling controls
Depyrogenation, sterile packing, filling, and closing. 
9
Holding and distribution
Facilities
10
Laboratory controls
Analytical methods 
11
Records and reports
Computer systems 
12
Returned and salvage drug products 
Batch processing
PROTOCOL FOR PROCESS VALIDATION:
The protocol for process validation is given from the tables 2, 3, 4 & 5 as follows

Table 2: Protocol for title page in industry

Name of the company
Process validation protocol
Product:
Page No. : 1 of …….
Protocol No. :
Version No. : 
Product name :

Label claim :

Master Formula Record (MFR) No. :

Batch Manufacturing Record (BMR) No. :

Effective Date :


Table 3: Protocol approval


Prepared By 
Checked By 
Approved By
Signature





Date





Name





Department
Quality Assurance
(QA)/Research and development (R&D)
R & D
Production
Quality Control
Head – QA


Table 4: Table of contents

Sr. No.
Title
Page No.
1.
Protocol Approval Sheet

2.
Table of contents

3.
Objective

4.
Scope

5.
Validation term and responsibility

6.
Steps for validation and acceptance criteria

7.
Process flow chart

8.
Procedure

9.
Form – A : Review of raw material/packing material

10.
Form – B : Evaluation of active raw material

11.
Form – C : Evaluation of inactive raw material

12.
Form – D : Qualification of equipment

13.
Form – E : Test instrument calibration

14.
Form – F : Dry mixing

15.
Sampling point diagram of RMG

16.
Form – G : Wet mixing

17.
Form – H : Drying

18.
Sampling point diagram of FBD

19.
Form – I : Lubrication

20.
Sampling point diagram of RMG

21.
Form – J : Compression

22.
Form – K : Coating

23.
Form – L : Bulk packing

24.
Re validation criteria

25.
Change control

26.
Stability

27.
Deviations

28.
Conclusion

29
Report and Approval

Table 5: Validation team and Responsibilities

Department   
Designation
Responsibility
Research and
development (R&D)
Executive/Officer
To coordinate the entire validation process by scheduling meetings and discussions with production, quality control and quality assurance.
Preparation of preliminary validation protocol, master formula record, monitoring the process, compiling and analyzing data and test results and preparing the final report.
To review the preliminary validation documents.
Quality assurance
Officer
To coordinate the entire validation process by scheduling meetings and discussions with the team.
Preparation of validation protocol, monitoring the process,
compiling and analyzing data and test results and preparing the final report.
To review of validation documents.
Production
Officer
To participate in performing the validation steps during manufacturing processes.
To assist in collection of data.
Quality control
Officer
To test and report the test results
Quality assurance
General manager 
Quality assurance
To approve the process validation protocol and report.
To review of validation documents.
To approve the process.


STEPS FOR VALIDATION AND ACCEPTANCE CRITERIA:
The following steps (Table 6) are used in industry for validation of tablets in wet granulation process:
Table 6: Steps for validation and acceptance criteria in wet granulation process
Sr. No
Steps
Control Variable
Critical Parameters
to be checked
Acceptance criteria
1
Dry mixing
Time ….
Mixing time and
speed
Mixing time: ………………min.
Impeller speed: (slow/medium/high) ± 5RPM.
Content uniformity :90%-110%
RSD : ±5%
Impeller speed. 
2
Binder preparation and addition
Time
Mode and time of
addition
Depending up on the formulation
Temperature,  solvent used

3
Kneading
Time
Mixing time and
speed
Impeller speed : (slow/medium/high)
Chopper speed: (slow/medium/high)
Depending up on the formulation.
Impeller speed &
chopper speed
4
Drying
Inlet/outlet
temperature & time
Inlet/outlet
temperature &
Drying time
Initial drying:………. C
Drying time: ……………min.
Final drying : ……
0C±50C
Loss on drying : ……….% below 3% or depending
on formulation
5
Lubrication
Time
Mixing time and
speed
Mixing time: ……………min.
Speed: slow….rpm.
Content uniformity:
Physical parameters – for information.
Blender/granulator
speed
6
Compression
Pressure and turret
speed
Machine speed and
compression
pressure
Average weight: mg±5%,7.5%,10%.
Uniformity of weight mg : 
Thickness : ………….mm
Hardness : …………..KN or Kg/cm2
 Disintegration time: NMT…..min.
Friability : NMT…………%w/w
Assay : As per the label claim
Dissolution:…………….%
7
Coating
Pan speed and spray
rate
Pan speed
Inlet & outlet
temperature
Spray rate
Average weight:....mg±5%
Weight of 20 tablets: ….…..mg
Thickness : ………….mm
Disintegration time: NMT…..min.
Assay : As per the label claim
Dissolution: …………. %

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