Establishment of acceptance criteria

The Cleaning Validation should demonstrate that the procedure consistently
removes residues of the substance previously manufactured down to levels that
are acceptable and that the cleaning procedure itself does not contribute
unacceptable levels of residual materials to the equipment. The limits set
should be practical, achievable and justifiable.
In Active Pharmaceutical Ingredient manufacture there may be partial reactants
and unwanted by-products which may not have been chemically identified.
Therefore, it may be necessary to focus on by-products as well as the principle
reactant. Companies should decide on which residue(s) to quantify based on
sound scientific rational.
Chemical determination
It is generally the residual Active Pharmaceutical Ingredient or intermediate,
which is of greatest concern rather than reaction side products or residual
impurities.
There are a number of options available when determining acceptance criteria.
Where either toxicological or therapeutic data if available then calculation A or
B is preferable. If data is not available for either of these calculations or if the
result is more stringent calculation C should be used.
A. Limiting the level based on toxicity data.
An Acceptable Daily Intake (ADI) is calculated with suitable safety
factors applied and this is converted to the maximum allowable
carryover to the API.
B. Pharmacological Dose Method:
The philosophy is to reduce the levels of residual product in each piece
of equipment, such that no greater than 1/1000 of the normal
therapeutic dose will be present per typical dose of the next product to
be run in the equipment. The validation protocol should include a
calculation, which ties this philosophy to the acceptance criteria for the
samples to be tested.
C. Limiting the level of product which could appear in the following
products.
Limits from 10ppm up to 0.1% (based on the ICH impurity document
which indicates that up to 0.1% of an individual unknown or 0.5% total
unknowns material may be present in the product being tested )
Note FDA Statement on 0.1% impurities
Guide to Cleaning Validation in API plants

FDA statement: P. Alcock, in Human Drug cGMP Notes, P. Motise,
June 98: „...we have found that some firms have incorrectly applied as
their acceptance limit the 0.1% impurity identification threshold as
discussed in both the ICH impurity guideline and the U.S.P. General
Notices. This application of the 0.1% impurity threshold is
inappropriate because the limit is intended for qualifying impurities that
are associated with the manufacturing process of related compound and
not extraneous impurities caused by cross contamination. ...“ ) may be
used depending on the stage of the process.
It is also necessary to evaluate the ability of the cleaning procedure to
remove any cleaning agents introduced. The acceptance criteria for the
residual-cleaning agents should reflect the absence of these materials,
within the range of the capabilities of the assay and sampling methods.
The individual company must decide on the Acceptance Criteria which
are justifiable for their particular situation.
Physical determination
There should be provision during routine cleaning for a visual examination of
the equipment, verifying that it is free of visible residues. The validation
protocol should include this requirement as an acceptance criteria. During
validation, special attention should be given to areas that are ‘hard to clean’
(e.g. agitator shafts, thermowells, discharge valves etc.) and areas that would
be difficult to verify on a routine basis.
Microbiological determination
Appropriate studies should be performed (e.g. swabs and/or rinse sampling)
where the possibility of microbial contamination of subsequent product is
deemed possible and presents a product quality risk.

Elements of cleaning validation

A brief outline of the various elements of a basic cleaning validation study is given
below .
This is followed by a more detailed view of the individual elements in this section.
I. Establishment of acceptance criteria
II. Cleaning procedure
· Identification of the equipment
· characterization of the products (Previous: activity/toxicity,
solubility, subsequent: dosage, lot size)
· determination and characterization of the cleaning agents
III. Analytical method and its validation
IV. Sampling Procedure and necessary validation of same
V. Validation protocol
VI. Validation report

Cleaning validation Potential residues

The Active Pharmaceutical Ingredient Industry involves (in general) the manufacture of
Active Pharmaceutical Ingredients by both chemical and physical means through a
series of multiple step processes. Plants or individual pieces of equipment, including
ancillary equipment, may be used in multi-product manufacture or dedicated to
individual products.
The result of inadequate cleaning procedures is that any of a number of contaminants
may be present in the next batch manufactured on the equipment such as:
1. Precursors to the Active Pharmaceutical Ingredient
2. By-products and/or degradation products of the Active Pharmaceutical
Ingredient
3. The previous product
4. Solvents and other materials employed during the manufacturing process.
5. Micro-organisms
This is particularly the case where microbial growth may be sustained by the
product.
6. Cleaning agents themselves and lubricants

LAN VALIDATION.

LAN Qualification is the process of establishing appropriately documented verifications and tests that provide a high level of assurance that a computer system will operate in accordance with predefined specifications. The specific approach to be used for each level of qualification should be outlined in the project validation plan and needs to focus on the critical parameters, data, and functionality of thecomputer system. While there are no absolute lines to be drawn between qualification testing of a computer system , it is recognized that the qualifications listed below provide the necessary control and continuity throughout the validation life cycle and must be approved for the system to be released for use in the GMP environment.

a) Design qualification

b) Installation qualification

c) Operational qualification

d) Performance qualification

A Local Area Network is required to operate a server centric environment where devices (PCs etc.) positioned throughout a site buildings can connect to servers that provide specific services (print services, file services etc.). To facilitate this environment they must include one or more Gigabit routing switches which are configured in a fault tolerant configuration, providing automatic routing switch fail-over (hot redundant standby through industry standard Virtual Router Redundancy Protocol or Standby Routing Protocol). The system implements “Hot-swappable” chassis modules, allowing I.T. personnel to swap any failed module without interruption to the network.

These Gigabit switches form the core network backbone.

The backbone in turn has departmental edge switches connected into the overall backbone and again a fault tolerant configuration is implemented on the majority of these systems to enable LAN Validation..

Key Objectives.

1) Ensure that I.T. operate as a highly valued strategic asset to the company.

2) Implementation of a quality and reliable LAN Backbone.

3) Maintain full compatibility with installed base of IEEE 802.3 Ethernet nodes.

4) Implementation of IEEE 802.3z (Gigabit Ethernet) for LAN Backbone.

5) Support and implementation of IEEE 802.1D Spanning Tree Protocol.

6) Implementation of monitoring tools to establish key quality and performance metrics of the LAN Backbone.

7) High availability.

8) High level of security.

9) Scalability. Capability of aggregating a high number of Gigabit links as the company expands allowing future bandwidth requirements to be sustained.

10) IP Traffic Prioritisation.

11) Backbone routing.

12) Fault-tolerant backbone.

13) 100 Mbps switched to the desktop.

14) n) Standardisation on one networking technology

VALIDATION MASTER PLAN (VMP)

VMP RATIONALE.

The VMP is a document that has never been mandatory, but is always one of the first documents a regulator asks to view. This is an extremely important document because in constructing it, many serious commitments and decisions have to be made. Program conceptions have to be mated to the User Requirements Specifications (URS), Level 1, 2 and or 3, these specifications have to be mated to the Validation Master Plan (VP or VMP). From these plans the Design Qualification (DQ), Installation Qualification (IQ), the Operational Qualification (OQ), and the Performance Qualifications (PQ) have to be authorized, authored, approved for content, and issued for execution. The completed documentation has to be reviewed and accepted as complete by persons authorised to execute this role. All of these functions must be detailed in the VMP, when the project concept demands that avalidation master plan is required, or the Validation Plan (VP) where it does not. Responsibilities have to be declared, people have to be nominated, and everyone involved is duly served with a copy that carries the full authority of the company. The prospective progress of the project is there for everyone to compare to the actual progress. The VMP) is a document that documents the way the company will operate, who has control over the various aspects of the validation activities, and how production, quality control, and man management will be directed.

VMP SCOPE.

The document should cover the following subjects but should not limited to them alone:

• Introduction.
  
• Plan Origin and Approval.
  
• Derivation.
  
• Scope of Validation Activities.
  
• Validation Objectives.
  
• Validation Plan Review.
  
• Roles and Responsibilities.
  
• An Overview of Activities.
  
• Division of Responsibilities.
  
• System Description.
  
• Overview of System.
  
• Overview of Process.
  
• System Description.
  
• Validation Approach.
  
• Site Activities.
  
• Documentation and Procedures.
  
• Scope of Documentation.
  
• Validation Schedule of Activities.
  
• Project Master Schedule.
  

VALIDATION MASTER PLAN
IN THE QUALIFICATION PROCESS.