Validation Master Plan 2016-2017

1 OBJECTIVES OF THE DOCUMENT

The cleaning processes must be validated to confirm the efficiency of the method. The cleaning
validations are done for the equipment in direct contact with the products.
The analytical methods used to research the contaminants must be validated, with a sensitivity and a
detection limit acceptable.
Acceptable acceptance criteria for cleaning reagent and product residue must be specifically calculated
and reached in practice.
The cleaning validations are performed three times to be validated.
The validation using the placebo method is exceptionally allowed if the product is toxic or deteriorates
easily.
The test until clean method is not allowed.

1.1 REFERENCES
EC-GMP, vol. 4, Guidelines for good manufacturing practices for medicinal products for human and
veterinary use, Annex 15.
FDA Code of Federal Regulations, part 211, Current good manufacturing practices for finished
pharmaceuticals, 2010, part D, paragraph 211.67 Equipment cleaning and maintenance.

2 SCOPE

3 RESPONSIBILITIES
R&D states:
-

the cleaning reagent, if one is needed

the solubility of the product tracers in water or in the cleaning reagent added to water
the analytical methods that can be used to test the tracers

Production states:
-

if the material is compatible with the cleaning agent

if the material is easy to clean

Quality Control Laboratory states (and validates if necessary):

-

the analytical methods

the detection and quantification limits

Production and QC state:

-

the critical points to sample in the material

the sampling method

Depending on the above data: Production states:

-

the technical, human and logistic feasibility

the cleaning process

Production and QA state for each material the batch sizes to take into consideration for the residue limit
calculation.
Quality Assurance:
-

states the acceptance criteria

validate the cleaning processes
validate the sampling processes
validate the analytical processes
validate the documentation

4 DEFINITIONS AND GLOSSARY

In this document, and generally in the literature, the residue of contamination after cleaning is
considered as homogeneous on all equipment surfaces. All the calculations are made regarding that
principle.
However it is not always true. Prior to the validation, it is the validation team responsibility to check
every equipment parts, especially the small ones, in order to define if those parts could contaminate a
few daily dose of the product with a high concentration of residue.
In this case, the related parts will be considered with specific acceptance criteria, independently from
the rest of the equipment.
In case of major cross contamination risk, difficulty to clean or for economical reason, some parts of
equipment or full equipment can be dedicated to one product.

5 PREREQUISITES
All the equipment, analytical methods and staff must be qualified. Written SOP must exist, be clear,
detailed and applicable.
It is better to validate cleaning processes that have been optimized in order to reduce the costs:
-

number of rinsing cycles

need of a cleaning reagent

5.1 EQUIPMENT QUALIFICATION

Design qualification
Installation Qualification
Operational Qualification

5.2 PROCESS VALIDATION

Performance Qualification

5.3 FACILITIES QUALIFICATION

HVAC qualification
Purified water qualification
Room qualification

6 TYPES OF CLEANING PROCESSES, CLEANING REAGENTS

The cleaning can be done manually in the cleaning room or in place for equipment that cannot be
moved. The manual cleaning has a high variability of results. The staff member variability must be as low
as possible, which involves a good training of the staff, detailed, realistic and repeatable cleaning
processes, and repeating each cleaning validation three times.

6.1 CLEANING MATERIAL

The cleaning material must be adapted to the cleaning of the equipment. It must not be a source of
contamination. The particle release of the cleaning material must be known and nontoxic. They must be
approved for food contact. The supplier must guarantee their constant quality.

6.2 CLEANING REAGENTS

Cleaning reagents must be used only if the cleaning with water only is not enough. Their composition
must be known and allowed for food contact (nontoxic).
They must not deteriorate the surfaces they clean, generate of transfer contaminants.

The information needed for every cleaning reagent are:

-

The qualitative composition and certificate of analysis

Safety data
Instruction for use
Dosage method
Residue research method

The supplier must guarantee their constant quality.

6.3

TRAINING
The production staff that will be in charge of the cleaning must be included in the cleaning method
choice. Once the cleaning method is decided, the staff must be trained and assessed prior to the
cleaning validation on the related equipment. Each person taking part to the cleaning must be
documented.
Scheduled retraining must be performed to ensure the cleaning method is observed.

7 LIST OF EQUIPMENT
7.1 MULTIPRODUCT, MONOPRODUCT OR SINGLE USE EQUIPMENT
Multiproduct equipment are to be validated.
Monoproduct equipment are tested only for cleaning reagent residue. No cross contamination is
possible.
Single use equipment are not subject to cleaning validation.
All the equipment on site are cleaned manually.

7.2 EQUIPMENT LIST AND DESCRIPTION

The equipment criteria that will be used for grouping are the following:
-

Material (e.g. stainless steel 316L, 314L, silicon, aluminium)

Surface in direct contact with product
Wear: new product=1, slightly wear=2, quite wear=3, very wear=4

One table must be done for each type of equipment.

7.2.1 Tanks
Number

Name

Multi
product
Yes/No

Material

Surface in
Wear
contact with
product
(cm)

7.2.2 Blender
Number
Name

7.2.3

Multi
product
Yes/No

Material

Surface in
Wear
contact with
product
(cm)

8 PRODUCT LIST
The product criteria that will be used for grouping are the following:
Galenic form: tincture, syrup, cordial, glycerite, spagyric/zimpel, potency, cream, gel, powder
Water solubility: not soluble, slightly soluble
Clean ability: easy=1, quite easy=2, quite difficult=3, difficult=4
LD50 (mg/kg) if the product is toxic, otherwise the minimal daily dose from the literature
(mg/kg)

Part Name Compo- Galenic Smallest Water

Clean- cleaning LD50
no.
sition
form
batch
solubility ability reagent (mg/kg)
size (kg) (g/L)

Maximum
daily dose
(mg/kg)

OR
Part
no.

Name

Main or
most toxic
product =
tracer

Smallest
batch size
(kg)

Tracer
dose per
unit

Water
solubility
(g/L)

LD50 or
maximum
daily dose
(mg/kg)

Cleanability

9 DESCRIPTION OF THE GROUPING METHOD BY PRODUCT AND EQUIPMENT

FAMILIES
The GMP allow the grouping with reservations of not doing risked extrapolation.

The cleaning validation of one type of surface is only applicable to that type of surface. It is material
dependant.
The design and size of the equipment must be similar, or the proportionality must be demonstrated.
The groups can be large or small.
The grouping must be justified and documented.

9.1 GROUPING OF CLEANING PROCESSES

The first step is to state all the different cleaning processes.

9.2 GROUPING OF EQUIPMENT

The second step is to state every equipment cleaned with the same method.
Criteria for grouping equipment: Design, Size, Material

9.3 GROUPING OF PRODUCTS

Criteria for grouping product: Solubility, Clean ability, Toxicity/Activity

10 ESTABLISHING OF THE "WORST CASES", RISK ANALYSIS AND MATRIX, CHOICE

OF ONE OR SEVERAL "WORST CASES"
10.1 WORST CASE DEFINITION
The cleaning validation of the worst case involves the validation of the cleaning of all products and
equipment in the same families that are less critical.
To make the matrix, the fewer parameters must be used. They must not be redundant in order to not
false the calculation. The risk analysis must be based on the common sense, reality and simplicity.
The worst case is the most active or toxic and the most difficult to clean.
There can be several worst cases for the same equipment or cleaning method.
In case several batches of the same product are manufactured in a raw, the maximum number of
batches before the cleaning is needed must be stated and assessed during the cleaning validation.

10.2 PRODUCT-EQUIPMENT MATRIX

Product 1
Product 2
Product 3

Equipment 1
x
x

Equipment 2
x
x

Equipment 3
x
x
x

10.3 WORST CASES CHOICE

The worst cases are the following:
-

11 DEFINITION OF THE AFFECTED EQUIPMENT SURFACES

For closed production processes, all the inside surfaces (direct product contact) are affected to the
cleaning validation. The opened parts must be check to see if they can be source of contamination.
For opened production processes, only a risk analysis will state which surfaces are a risk of
contamination for the product.

12 APPROACH FOR NO DIRECT CONTACT SURFACES SUCH AS INCUBATORS

13 TYPES OF THE SEARCHED CONTAMINANTS

The first compounds to look for are the Active Pharmaceutical Ingredients, cleaning reagent residue and
microorganism. It must be stated for each product if some degradation products can appear during the
cleaning process and how toxic and clean able they are. They can become the tracer.

13.1 VISUAL MARKS

13.2 PRODUCT RESIDUES AND DERIVATE

13.3 CLEANING REAGENT RESIDUES

14 DEFINITION OF THE TIME STORAGE LIMITS ("HOLDING TIMES")

14.1 DIRTY EQUIPMENT HOLD TIME (DEHT)
The DEHT is the duration between the end of the production and the beginning of the cleaning. The
Production Department states the maximum duration the equipment can be stored dirty before the
cleaning starts. The DEHT has a direct impact on the cleaning process as the dirt can be more difficult to
clean when they are old. Moreover, the germs will have time to grow.
The storage conditions must be stated and avoid further contamination.
During the cleaning validation, the cleaning will start at the end of the DEHT. If the results do not
comply, the DEHT can be reduced.

14.2 CLEANED EQUIPMENT HOLD TIME (CEHT)

The CEHT is the duration between the end of the cleaning and the beginning of the next production. The
Production Department states the maximum duration the equipment can be stored cleaned before the
production starts.
A microbiological testing must be performed either only at the end of the CEHT, before production, or
on a regular schedule. However, the most sampling are performed, the higher risk of contamination.

15 SAMPLING METHODS (VISUAL, DIRECT, RINSING) AND SAMPLING PLANS

Direct sampling is expected by the GMP. The sampling plan states the pertinence of the samples.
Only if direct sampling is impossible, indirect sampling is allowed:
-

Sampling of the last rinsing water after cleaning

Sampling of an additional rinsing which can be with another solvent and less solvent
Soaking

[14]

15.1 DEFINING THE SAMPLING POINTS

15.1.1 Where?
Only the critical points need to be sampled. They are the parts of the equipment with a risk of
contamination. They depend on:
-

The design of the equipment (e.g. difficult to reach, embossed design)

The material (plastic is more difficult to clean than stainless steel)
The accumulation of the product

Classification according to clean ability:

-

Level 1: there is no seal, bend/angle, dead volume, total immersion.

Level 2: there is no seal, bend/angle, dead volume, partial immersion and parts not immerged
reachable OR there are seals, bends/angles, dead volumes, total immersion.
Level 3: there are seals, bends/angles, dead volumes, partial immersion and parts not immerged
not reachable.

Classification according to product accumulation:

-

Level 1: low product accumulation

Level 2: high product accumulation
Level 3: very high product accumulation

Criticality matrix for each part of the equipment:

Clean
ability

Level 1
Level 2
Level 3

Level 1
1
2
3

Product accumulation
Level 2
2
4
6

Level 3
3
6
9

The points that will be sampled are the ones with the highest criticality level.

15.1.2 How many?

The number of sampling points is determined according to the total surface of the equipment. If it is big,
there is more chance to have several sampling points. Each critical point must be sampled.
Each sampling point must be sampled 3 times and the analysis must be performed on the 3 samples.

15.2 SAMPLING METHODOLOGIES

The sampling material must not be a source of contamination, must not interfere with the equipment
surface or the product. It must not deteriorate the equipment surfaces, neither release contaminants on
the equipment.
The sampling material can be made of cellulose, polyurethane or polypropylene.

The sampling can be direct or indirect. The direct sampling is more reliable because it actually tests the
residues on the equipment while the indirect method only tests the residue taken off the equipment.
15.2.1 Direct sampling
The shape and the size of the surface to be sampled must be determined. There are 3 types of direct
sampling.
15.2.1.1 Contact sampling
For microbiological testing only. A contact box made of agar-agar and with a specific surface of 25cm is
pressed against the equipment surface.

15.2.1.2 Swabbing
For microbiological or residue. The sample is taken with a swab which is then put into a solvent with a
specific volume. A sterile fabric can also be used. It is either dry or soaked with a solvent. The swab is
wiped on the equipment surface. The surface must be dry.

Wipe the following way:

then

15.2.2 Sampling yield

The sampling yield must be calculated (recovery ratio) in order to proof that the sampling method
allows to actually sample the product.
1.
2.
3.
4.
5.

Put a specific quantity of the tracer (Q1) to be tested on the 25cm surface
Sample it the way that needs to be validated
Test it with the usual analytical method
Determine the dosed quantity (Q2)
Perform the analysis 3 times.

The recovery ratio is calculated as follow:

% =

2
100
1

If R% is 70% the 3 times and the relative standard deviation is < 10% the 3 times; then the sampling
method is validated.
15.2.3 Indirect sampling
For the cleaning reagent and product residue. The indirect sampling is made in addition to a direct
method. It cannot be the only sampling method.
15.2.3.1 Rinsing water
Indirect sampling relates to the rinsing water. For each sampling point the volume of water to be
sampled is defined.
15.2.3.2 Soaking
The small pieces are put in a solvent. They must be totally immerged. The contact time must be
specified.
15.2.4 Placebo
After the cleaning, a placebo batch is manufactured. Samples are taken at the beginning, middle and
end of the batch and residues are tested. This method is allowed only if it is the only possible one or is
the product is highly toxic.

15.3 TRAINING AND QUALIFICATION OF THE SAMPLERS

The sampling must be performed only by trained staff members.

16 ANALYTICAL METHODS
16.1 MICROBIOLOGICAL ANALYSIS
The seeding can be done by:
-

Membrane filtering

Direct seeding onto a breeding ground on a petri dish

The breeding ground are then put into the incubator and the colony-forming units are counted.
For residue testing the solvent can then be concentrated.

17 ESTABLISHING OF THE ACCEPTANCE CRITERIA

Three parameters are to be tested after cleaning: visual cleanliness of the equipment, microbiological
contamination and residue of the previous product and of the cleaning reagent.

17.1 VISUAL CRITERIA

The first criteria to be checked is the visual cleanliness. This is the aim to achieve at the end of the
cleaning process. It is assessed by the Production staff doing the cleaning, and the assessment follow the
4-eyes principle. The second person can be another staff member, the manager or someone from the
validation team.
The equipment is visually clean if there is no mark visible to the naked eye. It is known that the products
get visible to the naked eye from 100g/cm, depending on the observation conditions.[15] Basically, if
the staff can see any mark, then the test fails. If not, the test passes.
The staff must be trained to know what to look for.
The visual cleanliness can be the only assessment criteria only between two batches of the same
product.

17.2 MICROBIOLOGICAL CONTAMINATION CRITERIA

The microbiological testing are the same as the ones performed on site for the raw materials or final
product. They comply with the Ph. Eur. 2.6.12 and 2.6.13.
The acceptance criteria are the following:
-

Total count: max 10 000 000 CFU/g

Fungal count: max 100 000 CFU/g
Coliform: Record

E. Coli: 100cfu/g
Salmonella: absent

Usually companies use the following limits:

-

Total count: 20ufc/cm

E. coli: absent
Salmonella: absent

17.3 RESIDUE CRITERIA

Those calculation must be done for calculating the residue of the previous product and the residue of
the cleaning reagent. Both must be tested.
17.3.1 10ppm criteria
This criteria states that there must be no more than 10 parts of the product A in a million parts of the
product B (no more than 10mg of A in 1kg of B). It is uttered in milligrams. A can be either the previous
product or the cleaning reagent.
The Acceptable Residue Limit (ARL) is calculated as follow:
=

10

[]

B [kg] = minimum batch of the product B

S [cm] = surface of the equipment in direct contact with the products A and B (shared surface)
ST [cm] = total surface of the equipment
17.3.2 Thousandth criteria
This criteria is based on the risk of founding a certain concentration of the product A in a daily dose of
the product B. To be in the worst case, the concentration of A is divided by a safety factor which is 1 000
for oral products. The quantity of B has to be the maximum daily dose, because the more you take of B,
the more you have chance to get residue of A that are in B.
The concentration will either be the minimum therapeutic daily dose of A if it is an API, either the LD50 if
the product do not have an activity (excipient).
17.3.2.1 Criteria based on the minimum therapeutic daily dose
This calculation can be done with the previous product, using the API.

1
[/]

I [mg] = minimum daily dose of A

SF = safety factor = 1 000 for oral product or 100 for topical products
J = number of units of B per batch (using the minimum batch size of B)

K = maximum daily units of B

S [cm] = surface of the equipment in direct contact with the products A and B (shared surface)
17.3.2.2 Criteria based on the toxicity
This calculation can be done with the previous product (using the excipients) or the cleaning reagent.
Calculation of the No Observable Adverse Effect Level (NOEL):
= 50 5 104 [/]
LD50 [mg/kg/day] = dose that kills half of the animal population that ingested the product.
Calculation of the Acceptable Residue Limit (ARL):
=

70 1

[/]

70 [kg] = mean weight of an adult.

SF = safety factor = 1 000 for oral product or 100 for topical products
J = number of units of B per batch (using the minimum batch size of B)
K = maximum daily units of B
17.3.3 Case of a criteria needed for indirect sampling
For indirect sampling which is for example a sample of rinsing water, the parameter S can be replaced by

with:

S [cm] = surface of the equipment in direct contact with the products A and B (shared surface)
ST [cm] = total surface of the equipment
The ARL will then be uttered in mg.
17.3.4 Choice of the best ARL
Both of the 10pp, and the thousandth criteria must be calculated. The ARL that will be used in the
cleaning validation is the smallest one.

18 VALIDATION PROTOCOL
1.
2.
3.
4.
5.
6.
7.
8.
9.

Introduction and objective

Responsibilities
Scope
Prerequisites
Dirty Equipment Holding Time
Cleaning process
Tests to be performed: Visual check
Sampling
Sample analysis

10. Acceptance criteria

11. Cleaned Equipment Holding Time
12. Appendixes for validation record

19 VALIDATION REPORT
The cleaning validation report must:
-

Summarize the cleaning process that has been implemented

Analyse the deviations to the protocol
State if the cleaning validation passed or failed
Be signed by QA

20 SCHEDULE 2016-2017

21 UPKEEP OF THE VALIDATED STATE OF THE SYSTEM, "CHANGE CONTROL",

PERIODICAL REVIEW AND POTENTIAL REVALIDATIONS
21.1 PERIODICAL REVIEW
The periodical review is to be done annually. It states all the deviations, non-conformities and change
control regarding the manufacturing process and the cleaning.
A simple trend review can be implemented in order to prevent any loss of control. Self-inspection must
be done regularly for manual cleaning.
The cleaning validation is assessed and the QA states if the cleaning is still validated or if a new
validation must be performed.

21.2 PERIODIC VALIDATION

The cleaning process are validated of a period of 3 years.
During this period, some random assessments and tests can be performed to insure the constant quality
of the cleaning.
At the end of the 3 years, the cleaning process is assessed. If no significant changes occurred, the
cleaning process is kept and the validation renewed automatically, without having to perform a new
validation.

21.3 CHANGES THAT CAN LEAD TO A NEW PROCESS VALIDATION

-

Changes regarding the cleaning process,

Changes regarding the origin of raw materials,

Changes regarding the product formulation and/or manufacturing process,
New products (see Figure 1),
Changes regarding the cleaning reagent formulation,
New cleaning reagent,
Changes regarding the equipment.

The consequences of any change must be assessed through a risk assessment. It will determine if a new
cleaning validation must be performed or not.

New product

Is its cleaning process the

same as the usual one?

No

New cleaning
validation

Yes
Is the product a worst
case in terms of clean
ability?
Yes

No

Is the product a worst

case in terms of
toxicity?
Yes

New cleaning
validation:
- new product
- new acceptance
criteria

Is the product a worst

case in terms of
toxicity?
No

New cleaning
validation:
- new product
- old acceptance
criteria

Yes

New cleaning
validation:
- new product
- new acceptance
criteria

No

Product included
in existing
validations

Figure 1: decision tree in case of a new product

22 REGULATORY AND LITERATURE REFERENCES

[1]
[2]
[3]

EMA - Annexe n 15 des GMP europennes (Eudralex vol. IV) (LD 15 des BPF)
EMA - Partie 2 des GMP europennes (Eudralex vol. IV)
ICH (International Conference On Harmonisation) ICH Q7

[4]

[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]

[13]
[14]

[15]

Pharmaceutical Inspection Co-operation scheme PI 006 3 "Recommendations on

validation master plan, installation and operational qualification, non sterile process validation
and cleaning validation" sept. 2007
FDA "Guide to Inspections Validation of Cleaning Processes" 1993
Parenteral Drug Association - Technical Report n 49 "Points to Consider for Biotechnology
Cleaning Validation" 2010
PDA (Parenteral Drug Association) - Technical Report n 29 12 "Points to Consider for
Cleaning Validation" Version 2012 rvise
Active Pharmaceutical Ingredients Committee "Guidance on aspects of cleaning validation in
pharmaceutical ingredients plants" dec. 2000
Active Pharmaceutical Ingredients Committee "Cleaning validation in pharmaceutical
ingredients plants" sept. 1999.
Socit Franaise des Sciences et Techniques Pharmaceutiques "Validation des procds de
nettoyage, rapport d'une commission SFSTP". S.T.P Pharma Pratiques 6 (1) 5-40 (1996).
Socit Franaise des Sciences et Techniques Pharmaceutiques "Validation des procds de
nettoyage. Rapport d'une commission SFSTP" . S.T.P Pharma Pratiques 10 (5) 270-273 2000.
Socit Franaise des Sciences et Techniques Pharmaceutiques "Mthodes de prlvement
et mthodes analytiques pour le contrle et ou pour la validation du nettoyage". S.T.P Pharma
Pratiques 10 (5) 270-273 2000.
A3P revue "La Vague" Frdric Laban "Nettoyage des salles propres, faut il valider ou non ?
Quels sont les points cls des GMPs ?" janvier 2006
http://a3p.org/index.php/articles-techniques-et-scientifiques/1154-cahier-pratiquestrat%C3%A9gie-de-validation-des-proc%C3%A9d%C3%A9s-de-nettoyagedes-%C3%A9quipements-de-production-en-industrie-pharmaceutique-la-vague-38.html
(consulted the 27/07/2016)
Fourman & Mullen