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Validation master plan

Here you will find answers to the following questions:

  • What is understood by the term validation master plan'
  • What different types of validation master plans may be compiled?
  • What is the benefit of the validation master plan for the management, for the validation manager/validation team or for externals (contractual partners, authorities)?
  • What are the essential elements of a validation master plan?
  • What does a validation matrix contain?
  • What is "bracketing"?
  • What is "matrixing"?
  • Which reasons may justify process validation of product families (product groups)?

The validation of processes and the qualification of buildings and apparatus as a prerequisite for the process validation requires a considerable investment in terms of personnel, time and money. The tasks at issue should not be carried out as a side job and require full support from the management board. It is therefore important to determine in writing the general strategy and philosophy of a company on the topic of validation from the point of view of the management board, e.g. in the form of a validation policy or validation philosophy. This rather general declaration of intent demonstrates the general attitude of a company regarding validation problems internally (management board, staff) and externally (customers, authorities).

The validation policy can be an independent document, part of a quality assurance manual or a validation master plan.

Beyond the general declaration of intent, the validation master plan documents the structured approach of a company to validation projects (see chapter 2 Example of a validation master plan). The official rules contain the definitions cited in figure 1.

Figure 1 Definition of a validation master plan

Definition of a validation master plan

In accordance with PIC/S PI 006 (4.3.1):
"A validation master plan is a document that summarises the firmґs overall philosophy, intentions and approach to be used for establishing performance adequacy. "

In accordance with Annex 15, EU GMP Guideline (2):
"All validation activities should be planned. The key elements of a validation program should be clearly defined and documented clearly in a validation master plan (VMP) or equivalent documents."

Figure 2 Function of the validation master plan

Function of the validation master plan

  • Obligation of the management board to execute the validations faultlessly and to provide the required resources (time, people and money)
  • Company-specific definition of terms
  • Company-specific implementation of legal requirements
  • Definition of a structured approach to qualification and validation projects, (key elements of the qualification and validation program)
  • Information about the general organisation of validation activities, responsibilities, delegated tasks, interfaces, controlling bodies
  • Overview of the individual validation projects, including time and cost planing

Pharamceutical companies tend to complain that there are no binding guidelines from the legislator for the procedure of how and when validations are to be carried out, and even terminology and contents vary. Quite the contrary, this should be considered as invaluable scientific and corporate freedom. After all, the most varied solution possibilities are conceivable - and each pharmaceutical company is permitted to define an individual validation strategy optimized to its own organisation and product range: the validation master plan is the correct place for defining and justifying a company's individual understanding of validation, as well as company-specific definitions and contents.

A VMP should also point out that validation is not understood as an isolated task, but rather as a continuous process, and should explain that (and how) the required GMP- environment is provided ( e.g. maintenance,, documentation, training, change control).

The type and content of the validation master plan can vary greatly (see chapter 3 Example for a validation matrix). A validation master plan can, for example, give a general overview of the qualification and validation work for a manufacturing site planned from scratch. In this case it is a useful planning tool for the project management, and scope and contents will differ significantly from other VMPґs, e.g. a validation master plan for a manufacturing facility in old buildings, producing a great variety of drug products already marketed for years, but which have never undergone a formally documented validation process. This type of validation master plan is primarily used to define rationales for bracketing, to set priorities and to evaluate the risk for products, where validation has not yet been performed.

If there is extensive validation work to be done for one product, it can be advantageous to write an individual validation master plan for this product in order to "unburden" the individual validation protocols..

In contrast, a validation master plan for a global corporate group has a completely different focus: the concepts and strategies valid for all country representations should be specified here - without being able to go into the local task assignments and responsibilities in much detail

Figure 3 Various types of validation master plan

Various types of validation master plan (VMP)

VMP as a part of project management

e.g. for the setting up and qualification of new manufacturing sites

Cross-project VMP

e.g. for a manufacturing facility with old preparations: for recording and grouping products

VMP as a global validation concept of a global corporate group

Determination of corporate strategies, terminology, acceptance criteria; additional, local master plans may be necessary

Product-related VMP

in case of extensive validation work for a product

.

Basic elements that each validation master plan should contain are specified in PIC/S PI 006 and appendix 15 to the EU GMP Guideline (see also figure 4).

The validation master plan should be clear and concise and not repeat the contents of other documents unnecessarily. Cross-references to existing documents are useful here instead. A validation master plan should be confirmed and approved by the management.

Figure 4 Elements of the validation master plan

Elements of the validation master plan (in accordance with PIC/S PI 006)

  • Validation policy
  • Organisation and responsibilities
  • Company-specific definitions
  • Description of the validation project (manufacturing site, building, facility, process, product)
  • List of the individual validation projects ("validation matrix"): building, facility, control equipment to be qualified, products, processes, systems to be validated
  • Key acceptance criteria or procedure for determining acceptance criteria
  • Documentation formats for validation plans and reports
  • List of relevant SOPs
  • Schedule and cost estimate, estimate of staffing (including training needs) and equipment
  • System for change control

The VMP as a summarising document provides external parties (clients, customers or the authorities) with the possibility of quickly gaining an overview of the validation strategies of a company. This aspect is particularly interesting for contract manufacturers because the validation often represents a part of the service provided.

1 Validation matrix

A validation matrix, as a component of the validation master plan, is a table which lists all products, processes or systems that have to be qualified or validated and allocates the required action to be taken:

  • Scale of the qualification (DQ, IQ, OQ, PQ)
  • Cleaning validation
  • Method of process validation (prospective, concurrent, retrospective)
  • Revalidation activities
  • Current status, future planning
  • Group/family formation; bracketing and matrixing

The individual activities in the matrix should be indicated with priorities and responsibilities and enable an overview of complex validation projects (PIC/S PI 006).

Formation of product families or product groups; bracketing and matrixing

In particular, when a large number of drug products are to be validated, already marketed for years, it is often necessary for reasons of time and cost to summarise the different strengths of a product or similar products during the process validation, in order to reduce the validation effort. In this case, there are various strategies:

Matrixing: By this approach, the manufacturing processes for various strengths of the same drug product are validated together. The formulations and manufacturing processes must be the same. If there are differences in the composition or manufacturing processes, a risk analysis must be carried out to evaluate the effects that this could have on the validation result. Fewer than three validation batches can be manufactured for each strength if this is scientifically justified in the validation master plan or in the validation protocol. It is not advisable, however, to produce no validation batches at all from individual (e.g. the middle) dosages, because the FDA wants to see the validation of a - no exact figures - "minimum number of production batches for each strength".

Family grouping: This concept is intended to create a combined validation protocol for validating the procedure for different but related drug products.

In this case, it is of particular importance to thoroughly justify why the drug products grouped together into a product group may be validated together. All variations in the formulation or method of manufacture must be described and evaluated in detail (risk analysis). If, however, there are major variations in the equipment used or the procedures performed, each drug product has to be validated separately.

Bracketing: The bracketing concept considers only extreme cases, e.g. the worst case scenario. This may include, for example, preparations with the highest and lowest dosage, drug substances with the best and worst water solubility, the lowest and highest mixing load, the best and worst flow capabilities, etc.

To use the bracketing concept for the process validation, note that a well-justified written reasoning must be submitted to explain why the opinion is that the intermediate strengths, preparations, loads or other features can be extrapolated from the results for the extreme cases. Despite this, a minimum number of production batches must be included in the validation for each drug product and each dosage. This minimum number, however, has not yet been defined and can be determined and justified individually.

For all three procedures, the pharmaceutical company is obliged to develop and justify a procedure suitable for the particular case and to consider similarities/differences between the various strengths or different drug products.

2 Example of a validation master plan

Pharmaceutical
company

Validation master plan

P. x of y

VMP-0815-4711

Validation master plan for Ixberg site

valid from 01.05.2003

1. Scope

This validation master plan applies at the Ixberg site for the process validation of solid dosage forms. It also refers to products manufactured at a contract for other pharmaceutical companies. Furthermore, it is the basis for the process validation of products manufactured and validated by contract manufacturers for the Pharmaceutical company company.

This document is binding for all staff in the GMP area involved directly or indirectly in the manufacturing of solid dosage forms as well as external consultants on the payroll.

This validation master plan does not apply for bio-technological products manufactured from 2004 in the new facility B6780. The procedure for these products is regulated in a separate validation master plan.

This validation master plan does not include the cleaning validation and computer validation. The procedures for the cleaning validation and computer validation are defined in separate validation master plans.

2. Key terms

Validation master plan, process validation, validation manager, validation team, validation matrix, statistical techniques, revalidation, qualification, prospective validation, retrospective validation, concurrent validation, change control, deviations, raw material quality, product groups, matrixing, bracketing, contract manufacturers, critical processing steps, testing schedule, acceptance criteria, risk analysis, failure cause analysis, product file, annual product review, APR


compiled


(Date/signature Validation manager)


checked


(Date/signature Head of Production)


approved


(Date/signature QA management)


authorised


(Date/signature Managing director)

3. Content

1. Scope page 6

2. Key terms page 6

3. Content page 7

4. Validation policy page 8

5. Organisation and responsibilities page 8

6. Company-specific definitions page 10

7. Format of documents and archiving page 10

8. Description of project page 11

9. Family grouping, bracketing and matrixing page 11

10. Quality of the raw materials used page 12

11. Qualification status of the facilities and equipment used,
including measuring instruments page 12

12. Validation of analytical methods page 12

13. Risk analysis page 12

14. Critical processing steps and process parameters page 12

15. Determination of the test plan page 13

16. Determination of the acceptance criteria page 13

17. Sampling plan page 14

18. Reference documents page 14

19. Schedule page 15

20. Techniques for test interpretation page 15

21. Changes to the validation protocol page 15

22. Control of changes to validated processes or systems page 16

23. Distribution list page 16

24. Change history page 16

Appendices:

Appendix 1: Validation matrix including schedule and capacity estimate
(see chapter 3 Example for a validation matrix)

Appendix 2: Test plan
(see chapter 4 Example for a test plan)

Appendix 3: Distribution list
Maximilian Maier, Marlies Eberl
Uwe Paulus, Elisabeth Ober

4. Validation policy

It is an aim of Pharmaceutical company to exclusively manufacture products for trade whose manufacturing procedure is reproducible, so that defective batches, overhauls and waste can be avoided and the health of patients is never put into jeopardy.

An important tool for achieving this aim is the process validation, which is a basic element of the Pharmaceutical company quality assurance system. The validation process involves all measures and their documentation which prove that procedures and processes yield reproducible products that correspond to the previously defined specifications. A prerequisite is that the building, facilities, equipment, machines, computers, staff and suppliers of raw material involved are suitable (qualified) for the intended use.

With our concept of process validation, we want to comply with legal requirements and meet the expectations of our customers with the obligations resulting from our ISO 9001-2000 certification.

5. Organisation and responsibilities

The head of production is responsible for process validation at Pharmaceutical company. He provides the necessary capacities and guarantees the time frame in production planning required for the validation. The head of production approves the master production record to be validated. He delegates coordination and execution of validation projects to the validation manager responsible. The validation manager appoints project-specific validation teams, made up of representatives from the relevant departements (pharmaceutical production, quality control, engineering, regulatory affairs department, etc.) and a member from QA. These teams can also be assisted by external consultants if necessary. Decisions are made by the team and approved by the validation manager after consulting the head of production.

If necessary, each validation project can be divided into further validation projects. Each individual project can be managed and processed by the corresponding specialised departments.

All staff involved in the planning and execution of the process validation must be able to demonstrate profound knowledge in the area of validation - additional to the regular GMP training (SOP 700-120-03 GMP training plan) - and with regards to validation master plans and validation protocols at Pharmaceutical company. The validation team is responsible for identifying training shortfalls and the training coordinator is responsible for organising the training.

To guarantee that the resources necessary for planning and executing the validation projects are provided, the validation master plan is finally authorised by the general management.

Tasks of the validation team:

  • to determine the scope and the extent of the validation work
  • to perform risk analyses
  • to compile a validation protocol and test plans
  • to set priorities for execution
  • to plan time and resources
  • to suggest changes to the validation protocol where necessary
  • to carry out validation work or establish subteams to carry out the validation work
  • to evaluate the validation results
  • to generate the validation report
  • to suggest possible follow-ups
  • to identify requirements for training as necessary

Tasks of the validation coordinator:

  • to compile and update a validation master plan
  • to appoint validation team(s)
  • to report to the head of production/customer
  • to check validation plans/reports and any changes
  • to define the distribution list for the validation documents
  • to coordinate validation projects as regards time and capacities
  • to ensure a smooth procedure and good information flow
  • to make all departments involved aware of validation plans and any planned changes before approval
  • to monitor compliance with schedules
  • to inform training coordinators of requirements for training

Tasks of the head of production in this context:

  • to approve the master production record to be validated
  • to check the validation master plans
  • to approve validation plans/reports and any changes or suggested follow-ups
  • to provide capacities for carrying out validation projects and necessary training
  • to approve/make decisions, e.g. in the case of required changes to the formulation or process changes
  • to submit planned changes to validated processes to the validation team for cost estimation

Tasks of the Qualified Person in this context:

  • to approve the master production record to be validated
  • to approve validation master plans/reports and any changes or suggested follow-ups

6. Company-specific definitions

Process validation is establishing documented evidence that production or packaging procedures are highly likely to consistently produce a product compliant with the specifications. The term "process validation" is not used at Pharmaceutical company for the cleaning validation or validation of analytical methods or for qualification steps. The validation process involves all measures and their documentation which prove that procedures and processes yield reproducible products that correspond to the previously defined specifications.

Qualification is documented evidence of the suitability of buildings, facilities, equipment, machines, computers, staff and suppliers of raw materials for the intended use. Successful qualification is a prerequisite for the execution of process or method validations. The qualification of buildings, facilities, equipment, machines and computers is a process of several consecutive steps; the individual steps are described in the qualification master plan QMP 9907834.

Prospective validation is applied for all new processes or newly-developed products. The general procedure for prospective validation is regulated in the SOP 100-200-01 Prospective validation of a new manufacturing procedure.

Retrospective validation is restricted to those drug products already marketed for long time, which have never undergone formal documented validation up to now. The prerequisites to be met and criteria to be fulfilled so that a process validation can be executed retrospectively are regulated in the SOP 100-210-01 Retrospective validation of manufacturing procedures for old drug products.

Concurrent validation is only possible in few cases that are to be well justified in writing. The details are regulated in the SOP 100-230-01 Concurrent validation of manufacturing procedures for transfer to other sites or in the case of slight changes to the procedures.

„Critical" factors, processing steps or parameters are those, where a slight change to this parameter or its environment has a significant influence on the process reliability or the quality of the final product. Critical factors are identified with the aid of risk analysis.

For further definitions, see the SOP 200-100-03 Definitions and terms.

7. Format of documents and archiving

All documents created as part of the validation procedure must correspond with the specifications in the SOP 100-505-02 Creation of validation documents and the respective current templates in the Intranet under Pharmafirma\QA\database\templates\Validation. This also applies for validation documents created by external companies. However, in some cases, it is possible to copy test plans and test reports from external companies into the validation documentation. A prerequisite is that these documents have cover sheets in the format used by Pharmaceutical company. This is the only way to guarantee unique identification and archivability in the Pharmaceutical company archiving system in accordance with the SOP 100-510-04 Archiving GMP-relevant documents.

8. Description of project

Each validation protocol must include a precise description of the product and the process to be validated in the form of a flow chart. A number must be assigned to each processing step (see SOP 100-505-02 Creation of validation documents) so that this step can be referenced unambiguously.

This VMP applies for the following four product groups:

  • Product group 1 - Powder and effervescent granulates: This involves powder mixtures or wet granulates intended to be dissolved and taken orally and filled in sachets.
  • Product group 2 - Tablets, film coated tablets and sugar coated tablets: The tablet cores in this product group are manufactured by direct compression, dry or wet granulation. Film coated tablets are coated with a solvent-free coating and sugar coated tablets are coated with a sugar-free coating.
  • Product group 3 - Pellets: Pellets are manufactured by means of extrusion and spheronisation. The pellets for a modified dissolution are coated with a solvent-free coating. Pellets are mixed according to the desired release profile and encapsulated in hard gelatine capsules.
  • Product group 4 - Hard gelatine capsules: Granulates (manufactured by wet or dry granulation) and/or pellets are encapsulated in hard gelatine shells.

All process validation projects to be carried out within the scope of this VMP, including schedules, priorities and capacity estimations are listed in appendix 1 (see chapter 3 Example for a validation matrix).

9. Family grouping, bracketing and matrixing

In order to reduce validation workload, it is possible to define product groups, equipment groups or groups with similar production processes. However, there must be a written, scientific rationale in any case. This approach allows to define and validate the "worst case" within each group, e.g. the most demanding product, the most complicated equipment, the most complex manufacturing procedure, the most unfavourable batch size).

It is also possible to address various dosages of a drug product in the same validation protocol according to a bracketing or matrixing concept, as long as the formulation and manufacturing procedure are comparable.

Prerequisites for the application of bracketing/matrixing or family grouping:

  • Evaluation of differences in dosage/formulation/procedure/equipment including risk analysis
  • Written justification in the validation protocol
  • Basically, at least one validation batch must be manufactured for each product and dosage - also when applying the bracketing/matrixing or product group concept.

10. Quality of the raw materials used

The specifications of the raw materials to be used and the suppliers approved for each raw material are documented in the respective validation protocol. For common raw materials, the specifications and suppliers usually used at Pharmaceutical company should be preferred. If it is necessary in some cases to define exceptional specifications or suppliers for a particular validation project, this must be justified in the validation protocol. The suppliers listed in the validation protocol must be qualified.

11. Qualification status of the facilities and equipment used, including measuring instruments

The validation protocol must list in detail all machines, facilities, measuring instruments and recording instruments used. The exact equipment type and, if necessary, size must be fixed because the result of the process validation is always only valid for the facilities and machines used in the validation runs. Transferability to similar or other equipment must be proven, where necessary, with revalidation. The qualification status of each of these pieces of equipment must be documented in the validation protocol. The calibration status of the measuring instruments should also be noted.

If alternative equipment is permitted for certain processing steps, e.g. different types of blenders, this must be explained in the validation protocol. The validation must be planned in such a way that suitable data material is collected for all specified types of blenders. In this case even more than three validation batches may be required.

12. Validation of analytical methods

Valid analytical methods must be prepared for the testing defined in the validation protocol. The validation status of the analytical methods is documented in the validation protocol.

13. Risk analysis

(At least) one risk analysis is carried out before or during the creation of a validation protocol. As part of this risk analysis, possible deviations/failures are identified for each processing step and the significance of the effect of these deviations on the quality of the final product is assessed. The processing steps and critical process parameters identified in this way must be validated. For more details see SOP 100-640-01 Carrying out risk analyses. The results of the risk analysis are documented as described in the SOP and are part of the validation protocol as an appendix.

14. Critical processing steps and process parameters

As a result of risk analysis, the processing steps are divided into noncritical and critical. Critical processing steps require validation. A test plan, including testing criteria, a sampling plan and acceptance criteria must be created for each critical processing step.

15. Compliation of test plans

A test plan for each critical processing step is appended to the validation protocol, with detailed descriptions of the tests to be carried out as part of the validation (see chapter 4 Example for a test plan). These are basically investigations that are carried out for validation purposes in addition to the normal in-process controls specified in the manufacturing instructions.

Tests may include:

  • more frequent monitoring of process parameters
  • more frequent in-process controls
  • additional examinations, e.g. content uniformity or particle size distribution
  • control tests after intentionally built in events, e.g. prolonged holding times, reduced/increased production speeds. However, intentional process faults are avoided for reasons of cost and environmental protection.

The test plan must also establish:

  • the frequency of tests
  • sampling where necessary (amount, intended use)
  • test methods
  • acceptance limits

16. Determination of the acceptance criteria

The validation protocol and test plan list the expected results and acceptable ranges of variations. If the validation runs do not comply to these acceptance criteria, this may be a hint to the fact, that the process in not under control. Acceptance criteria must always be defined in advance, prior to the start of the first validation run. The appropriate selection of acceptance criteria is crucial for the outcome of the validation project and is therefore a core element of the validation protocol.

When drawing up acceptance criteria, the following must be taken into consideration:

  • Manufacturing instruction
  • Application dossier for marketing authorisation
  • Product specifications
  • Experiences and results from scaling-up, from the pilot plant and from development

17. Sampling plan

When planning the process validation, particular attention must be paid to the generation of detailed sampling plans and to correct sampling because unsuitable sampling rarely leads to a meaningful test result. For critical manufacturing levels in particular, it is of vital importance that there are precise explanations for whether, for example, samples are taken regularly during a manufacturing operation or from different places in the container. Required details in the sampling plan (cf. SOP 300-240-02 Sampling instructions and plans):

  • Place (where? top - middle - bottom)
  • Time (when? time, frequency or start-middle-end)
  • Type (how? using which instrument?)
  • Quantity (how many g, ml or pieces per sample?)
  • Number of samples (how many samples at each sampling point?)
  • Use (for uniformity of content, physical determination, residual moisture, etc.)
  • Packaging and storage (in the case of laboratory investigations)
  • Labelling (traceability of sample series)

The intended use must be noted for all samples. Samples must not be taken "just in case". In contrast, the test plan can allow for specific testing (e.g. content uniformity), e.g. 40 samples to be taken according to the plan, only 20 of which are to be tested initially and the other samples only to be analysed in a predetermined case (e.g. standard deviation exceeds xyz).

18. Reference documents

For a better understanding and clarity, each validation protocol and report must list the relevant reference documents, for example, standard operating procedures, development reports, reports about pilot batches, IQ/OQ/PQ reports, etc.

The following documents are valid together with this validation master plan:

1. the qualification master plan QMP 9907834

2. the following SOPs (the current versions):

  • SOP 100-200-01 Prospective validation of new manufacturing procedures
  • SOP 100-210-01 Retrospective validation of manufacturing procedures for old drug products
  • SOP 100-230-01 Concurrent validation of manufacturing procedures for transfer to other sites or in the case of slight changes to the procedures
  • SOP 100-500-02 Annual product review, APR
  • SOP 100-505-02 Creation of validation documents
  • SOP 100-510-04 Archiving GMP-relevant documents
  • SOP 100-640-01 Carrying out risk analyses
  • SOP 200-100-03 Definitions and terms
  • SOP 300-240-02 Sampling instructions and plans
  • SOP 400-500-02 Handling of OOS (out-of-specification)-results
  • SOP 400-600-03 Reporting, evaluating and carrying out planned changes
    (Change control)
  • SOP 700-120-03 GMP training plan
  • SOP 900-330-02 Statistical techniques for test evaluation

19. Schedule

Manufacturing validation batches takes considerably more time than routine production. It is important to take this aspect into consideration when scheduling production and to draw up a detailed schedule to prevent misunderstandings and bottlenecks. The three validation batches must be scheduled for manufacture on different days, with different staff or during different shifts, if possible, to make this as realistic as possible.

The schedule and capacity estimate for this VMP are found in appendix 1 (see chapter 3 Example for a validation matrix).

20. Techniques for interpretation of test results

In order to prevent validation results from being subsequently influenced by choice of questionable statistical techniques, the validation protocol and test plan must establish the methods and statistical testing to be used for the interpretation of the test results (cf. SOP 900-330-02 Statistical techniques for test evaluation).

The use of outlier tests is generally not permitted (exception: biological and microbiological tests in accordance with SOP 007-014-02). Significantly different test results are subject to the OOS procedure in accordance with the SOP 400-500-02 Handling of OOS (out-of-specification)-results. However, if this concerns deviations from the targets as part of the process validation rather than deviations from specifications, a written failure cause analysis is performed instead.

21. Changes to the validation protocol

If changes to originally planned procedures are necessary during the process validation, the validation protocol must be modified. Either the relevant test plan can be revised (new version number, reason for change), or a new version of the validation protocol can be composed, e.g. in the case of considerable changes.

Each change must be approved before being implemented. All staff involved in the validation work must be informed about the changes.

Planned changes to the formulation, process, facilities, buildings and analytical methods are also subject to the change control procedure in accordance with the SOP 400-600-03 Reporting, evaluating and carrying out planned changes (Change control).

22. Control of changes to validated processes or systems

As soon as a process or system is validated, i.e. the corresponding validation documentation has been approved by quality assurance, changes can be made to the process or system but only in accordance with the SOP 400-600-03 Reporting, evaluating and carrying out planned changes (Change control).

A product file is saved containing the following current results (with reference to original documents) for each product where process validation is complete:

  • changes to the formulation, process, facilities, software, specifications of raw materials, raw materials or product, packaging, etc.
  • results of all regular and exceptional approvals
  • results of stability testing
  • complaints and recalls
  • OOS situations
  • revalidation or requalification activities

This product file is evaluated yearly (at the latest during the month of the validation approval) in accordance with the SOP 100-500-02 Annual Product Review, APR to check whether the process can still be considered validated.

23. Distribution list

See appendix 3 for the current distribution list for this VMP.

24. Change history

  • First issued: 03.07.1998
  • Existing version: 01.05.2003. Complete revision of validation concept, modified to suit the new company structure, contract manufacturers are included in the VMP.

3 Example for a validation matrix

Pharmaceutical company

Validation matrix

P. x of xx

VMP-0815-4713

Appendix 1 to Validation master plan VMP-0815-4711 for Ixberg site

valid from 01.05.2003

All process validation projects to be carried out as part of VMP-0815-4711 are listed with time and capacity estimates and priorities in tables in this appendix (validation matrix). Matrixing, bracketing and prioritisation are based on individual risk analyses (RA-0815-9912 to RA-0815-9922).


compiled


(Date/signature Validation manager)


checked


(Date/signature Head of Production)


approved


(Date/signature QA management)


authorised


(Date/signature Managing director)

Figure 5 Validation matrix - Appendix 1  

Name

Product no.

Qualification
complete

Process
validation priority

product group

Time frame

Capacity
Staff days

Powder and effervescent granules

31XXX

         

bPowder

315258

yes

12

 

Dec. 03 - Jan. 04

20

cPowder

315269

yes

13

 

Dec. 03 - Jan. 04

30

dGranulates

315300

yes

4

Group A

Aug. -
Sep. 03

40

dGranulate forte

315325

yes

4

Group A

Aug. -
Sep. 03

see above

tablets - directly compressed

95XXX

         

r tablets

957834

yes

7

 

Oct. -
Nov. 03

25

s tablets

957869

yes

3

Group B

May -
Aug. 03

50

s-Retard tablets

957641

no

8

 

Oct. -
Nov. 03

15

t- tablets

957693

yes

3

Group B

see above

see above

t- tablets forte

957695

yes

3

Group B

see above

see above

u- tablets

959695

yes

9

 

Oct. -
Nov. 03

30

tablets
- from wet/dry granulates

94XXX

         

v tablets

947834

yes

10

 

Nov. -
Dec. 03

15

vRetard tablets

947847

yes

11

 

Nov. -
Dec. 03

10

w tablets

947941

yes

5

Group C

Sep. -
Oct. 03

30

w tablets forte

947943

yes

5

Group C

see above

see above

Film coated tablets

97XXX

         

xTabs

978634

yes

12

 

Jan. -
Feb. 04

25

yRetard tablets

978347

yes

13

 

Jan. -
Mar. 04

50

zLong tablets

978941

yes

14

 

Jan. - Feb. 04

30

Sugar coated tablets

99XXX

         

mSugar coated
tablets

998783

yes

15

 

Feb. -
Mar. 04

20

nSugar coated tablets

997834

yes

16

 

Feb. -
Mar. 04

25

Capsules

56XXX

         

eCapsules

569834

yes

17

 

Apr. -
May 04

40

fCaps long

569878

yes

18

 

Apr. -
May 04

20

gCapsules

569883

yes

6

Group D

Sep. -
Oct. 03

30

gCapsules forte

569884

yes

6

Group D

see above

see above

Pellets

66XXX

         

oPellets

667841

yes

1

Group E

May -
July 03

40

pPellets

667834

yes

1

Group E

see above

see above

pPellets retard

667342

yes

1

Group E

see above

see above

qPellets forte

667830

yes

1

Group E

see above

see above

qPellets retard

669878

yes

2

 

June -
July 03

20

qPellets long

669734

no

2

 

June -
July 03

30

Primary packaging: blister

 

957834

yes

19

Group F

May 04

15

 

957869

yes

19

Group F

May 04

see above

 

957641

no

20

Group G

June 04

20

 

957693

no

20

Group G

June 04

see above

 

957834

no

20

Group G

June 04

see above

 

957869

no

20

Group G

June 04

see above

 

957641

no

20

Group G

June 04

see above

 

957693

no

21

Group H

July 04

15

 

957695

no

21

Group H

July 04

see above

 

959695

no

21

Group H

July 04

see above

 

947834

yes

19

Group F

May 04

see above

 

947847

yes

19

Group F

May 04

see above

 

947941

yes

22

Group I

Sep. 04

25

 

947943

yes

22

Group I

Sep. 04

see above

 

978634

yes

22

Group I

Sep. 04

see above

 

978347

yes

22

Group I

Sep. 04

see above

 

978941

yes

22

Group I

Sep. 04

see above

 

998783

yes

23

Group K

Oct. 04

15

 

997834

yes

23

Group K

Oct. 04

see above

 

569834

yes

22

Group I

Sep. 04

see above

 

569878

yes

22

Group I

Sep. 04

see above

 

569883

yes

23

Group K

Oct. 04

see above

 

569884

yes

23

Group K

Oct. 04

see above

Filling of sachets

 

315258

yes

24

Group L

Sep. 04

20

 

315269

yes

24

Group L

Sep. 04

see above

 

315300

yes

24

Group L

Sep. 04

see above

 

315325

yes

24

Group L

Sep. 04

see above

 

669734

no

25

 

Oct. 04

10

Final packaging

 

957834

yes

26

Group M

May - June 04

30

 

957869

yes

26

Group M

May - June 04

see above

 

957641

no

27

 

July 04

10

 

957693

yes

26

Group M

May - June 04

see above

 

957834

yes

26

Group M

May - June 04

see above

 

957869

yes

28

Group O

July 04

15

 

957641

yes

28

Group O

July 04

see above

 

957693

yes

28

Group O

July 04

see above

 

957695

yes

26

Group M

May - June 04

see above

 

959695

yes

26

Group M

May - June 04

see above

 

947834

no

29

 

Sep. 04

10

 

947847

yes

30

 

Sep. 04

15

 

947941

yes

26

Group M

May - June 04

see above

 

947943

yes

26

Group M

May - June 04

see above

 

978634

yes

26

Group M

May - June 04

see above

 

978347

yes

26

Group M

May - June 04

see above

 

978941

yes

28

Group O

July 04

see above

 

998783

yes

28

Group O

July 04

see above

 

997834

no

31

 

Sep. 04

15

 

569834

yes

32

Group P

Oct. -
Nov. 04

20

 

569878

yes

32

Group P

Oct. -
Nov. 04

see above

 

569883

yes

32

Group P

Oct. -
Nov. 04

see above

 

569884

yes

32

Group P

Oct. -
Nov. 04

see above

 

315258

yes

32

Group P

Oct. -
Nov. 04

see above

 

315269

no

33

 

Dec. 04

15

 

315300

no

34

 

Dec. 04

10

 

315325

yes

32

Group P

Oct. -
Nov. 04

see above

 

669734

yes

32

Group P

Oct. -
Nov. 04

see above

Total

         

875

4 Example for a test plan

Pharmaceutical company

Test plan for
process validations

P. x of xx

VMP-0815-4715

Enclosure 2 for the validation master plan for solid dosage forms for the Ixberg site

valid from 01.05.2003

Validation project: example - tablets 0.5 mg
Processing step #: # 04 - Blending

Sampling:

1. For blending uniformity:
The blending process is interrupted at the specified times. The blending container is opened carefully. Using a stainless steel lance (sample volume 1 ml, int. no. 3434) three samples are taken from the upper edge area of the blending container, three samples from the centre area and three samples from the lower edge area of the blending container. The samples are emptied into prepared, numbered and dated small glass bottles (int. no. 5634).

2. For angle of repose
After taking the CU sample, use a stainless steel scoop (volume 200 ml, int. no. 3478) to take three samples of approximately 200 g each from the upper area of the blending container. The samples are emptied into and sealed immediately in prepared, numbered and dated small wide-necked bottles (int. no. 1537). Ensure that these samples are not agitated during transport to the control laboratory; note also cf. SOP 300-240-02 Sampling instructions and plans.


compiled


(Date/signature Validation manager)


checked


(Date/signature Head of Production)


approved


(Date/signature QA management)

Pharmaceutical
company

Test plan for
process validations

P. x of xx

VMP-0815-4715

Enclosure 2 for the validation master plan for solid dosage forms for the Ixberg site

valid from 01.05.2003

Batch

#03 06 135

# 03 06 136

#03 06 137

Batch size

500,000 pc

650,000 pc

500,000 pc

Equipment/machine

Fantasy blender I

Fantasy blender I

Fantasy
blender II

Machine parameters

  • Speed of rotation

200 UpM

250 UpM

150 UpM

  • Blending time

10, 15, 20 mins

10, 15, 20 mins

10, 15, 20, 25 min

Test parameters

     
  • Uniformity
    of mixture

yes

yes

yes

  • Angle of repose

yes

yes

yes

Sample number

  • Content Uniformity (CU)

3 * 9 samples:
(# 1 - 27)

3 * 9 samples
(# 37 - 53)

4 * 9 samples
(# 63 - 89)

  • Angle of repose

3 * 3 samples
(# 28 - 36)

3 * 3 samples
(# 54 - 62)

4 * 3 samples
(# 90 - 99)

Figure 6 Validation matrix - Enclosure 2 test plan

Acceptance criterion

Content Uniformity

Angle of repose alpha

Mean value

x = 98 - 102  % labelclaim

< 30°

Single values

no value < 95 % or > 105 %

no value > 40°

Standard deviation

srel < 1.5 %

srel < 2.5 %

Summary

The validation master plan (VMP) is a document required in the PIC/S guideline PI 006 and in appendix 15 of the EU GMP Guideline, which serves to structure and control the validation work. The general procedure for validation projects, responsibilities and company-specific terminology is defined in the validation master plan. The VMP can be structured in different ways according to the application area. A VMP can, for example, cover the corporate validation strategy of a global group, or concern only a single drug product. The VMP is used for internal and external communication.



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