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: …………. %