Validation Master Plan Template

Validation Master Plan 2016-2017

1 O

BJECTIVES 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 R

EFERENCES

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 S

COPE

3 R

ESPONSIBILITIES

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 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 D

EFINITIONS 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 P

REREQUISITES

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 E

QUIPMENT

Q

UALIFICATION Design qualification Installation Qualification Operational Qualification

5.2 P

ROCESS VALIDATION Performance Qualification

5.3 F

ACILITIES QUALIFICATION HVAC qualification

Purified water qualification Room qualification

6 T

YPES 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 C

LEANING 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 C

LEANING 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).

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 L

IST OF EQUIPMENT

7.1 M

ULTIPRODUCT

,

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 E

QUIPMENT 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 contact with product (cm²) Wear

7.2.2 Blender

Number Name Multi product Yes/No Material Surface in contact with product (cm²) Wear 7.2.3 …

8 P

RODUCT 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 no. Name Compo-sition Galenic form Smallest batch size (kg) Water solubility (g/L) Clean-ability cleaning reagent LD50 (mg/kg) 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) Clean-ability

9 D

ESCRIPTION OF THE GROUPING METHOD BY PRODUCT AND EQUIPMENT

FAMILIES

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 G

ROUPING OF CLEANING PROCESSES

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

9.2 G

ROUPING OF EQUIPMENT

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

9.3 G

ROUPING OF PRODUCTS

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

10 E

STABLISHING OF THE

"

WORST CASES

",

RISK ANALYSIS AND MATRIX

,

CHOICE

OF ONE OR SEVERAL

"

WORST CASES

"

10.1 W

ORST 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 P

RODUCT

-E

QUIPMENT MATRIX

Equipment 1 Equipment 2 Equipment 3

Product 1 x x

Product 2 x x x

10.3 W

ORST CASES CHOICE The worst cases are the following:

-

11 D

EFINITION 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 A

PPROACH FOR NO DIRECT CONTACT SURFACES SUCH AS INCUBATORS

13 T

YPES 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 V

ISUAL MARKS

13.2 P

RODUCT RESIDUES AND DERIVATE

14 D

EFINITION OF THE TIME STORAGE LIMITS

("

HOLDING TIMES

")

14.1 D

IRTY

E

QUIPMENT

H

OLD

T

IME

(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 C

LEANED

E

QUIPMENT

H

OLD

T

IME

(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 S

AMPLING 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

15.1 D

EFINING 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:

Product accumulation

Level 1 Level 2 Level 3

Clean ability

Level 1 1 2 3

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 S

AMPLING 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 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 25cm² 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:

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. Put a specific quantity of the tracer (Q1) to be tested on the 25cm² surface 2. Sample it the way that needs to be validated

3. Test it with the usual analytical method 4. Determine the dosed quantity (Q2) 5. Perform the analysis 3 times. The recovery ratio is calculated as follow:

𝑅% =𝑄2

𝑄1× 100

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 T

RAINING AND QUALIFICATION OF THE SAMPLERS

The sampling must be performed only by trained staff members.

16 A

NALYTICAL METHODS

16.1 M

ICROBIOLOGICAL ANALYSIS The seeding can be done by:

- 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 E

STABLISHING 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 V

ISUAL 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 100µg/cm², 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 M

ICROBIOLOGICAL 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/cm²

- E. coli: absent - Salmonella: absent

17.3 R

ESIDUE 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: 𝐴𝑅𝐿 =10 × 𝐵 × 𝑆

𝑆_𝑇 [𝑚𝑔] B [kg] = minimum batch of the product B

S [cm²] = surface of the equipment in direct contact with the products A and B (shared surface) ST [cm²] = 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.

𝐴𝑅𝐿 = 𝐼 𝑆𝐹× 𝐽 𝐾 × 1 𝑆 [𝑚𝑔/𝑐𝑚²] 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 [cm²] = 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):

𝑁𝑂𝐸𝐿 = 𝐿𝐷50 × 5 ∙ 10−4 _{[𝑚𝑔/𝑘𝑔]}

LD50 [mg/kg/day] = dose that kills half of the animal population that ingested the product. Calculation of the Acceptable Residue Limit (ARL):

𝐴𝑅𝐿 =𝑁𝑂𝐸𝐿 × 70 𝑆𝐹 × 𝐽 𝐾× 1 𝑆 [𝑚𝑔/𝑐𝑚²] 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

𝑆 𝑆𝑇 with:

S [cm²] = surface of the equipment in direct contact with the products A and B (shared surface) ST [cm²] = 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 V

ALIDATION PROTOCOL

1. Introduction and objective 2. Responsibilities

3. Scope

4. Prerequisites

5. Dirty Equipment Holding Time 6. Cleaning process

7. Tests to be performed: Visual check 8. Sampling

10. Acceptance criteria

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

19 V

ALIDATION 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 S

CHEDULE

2016-2017

21

UPKEEP OF THE VALIDATED STATE OF THE SYSTEM

,

"

CHANGE CONTROL

",

PERIODICAL REVIEW AND POTENTIAL REVALIDATIONS

21.1 P

ERIODICAL 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 P

ERIODIC 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 C

HANGES 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.

Figure 1: decision tree in case of a new product

22

REGULATORY AND LITERATURE REFERENCES

[1] EMA - Annexe n° 15 des GMP européennes (Eudralex vol. IV) (LD 15 des BPF) [2] EMA - Partie 2 des GMP européennes (Eudralex vol. IV)

[3] ICH (International Conference On Harmonisation) ICH Q7

New product

Is its cleaning process the same as the usual one?

New cleaning validation

Is the product a worst case in terms of clean

ability?

Is the product a worst case in terms of

toxicity?

Is the product a worst case in terms of toxicity? No Yes Yes No Product included in existing validations New cleaning validation: - new product - new acceptance criteria New cleaning validation: - new product - old acceptance criteria New cleaning validation: - new product - new acceptance criteria Yes No Yes No

[4] 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

[5] FDA – "Guide to Inspections Validation of Cleaning Processes" – 1993

[6] Parenteral Drug Association - Technical Report n° 49 – "Points to Consider for Biotechnology Cleaning Validation" – 2010

[7] PDA (Parenteral Drug Association) - Technical Report n° 29 12 – "Points to Consider for Cleaning Validation" – Version 2012 révisée

[8] Active Pharmaceutical Ingredients Committee – "Guidance on aspects of cleaning validation in pharmaceutical ingredients plants" – dec. 2000

[9] Active Pharmaceutical Ingredients Committee – "Cleaning validation in pharmaceutical ingredients plants" – sept. 1999.

[10] Société Française des Sciences et Techniques Pharmaceutiques – "Validation des procédés de nettoyage, rapport d'une commission SFSTP". S.T.P Pharma Pratiques 6 (1) 5-40 (1996). [11] Société Française des Sciences et Techniques Pharmaceutiques – "Validation des procédés de

nettoyage. Rapport d'une commission SFSTP" . S.T.P Pharma Pratiques 10 (5) 270-273 2000. [12] Société Française des Sciences et Techniques Pharmaceutiques – "Méthodes de prélèvement

et méthodes analytiques pour le contrôle et ou pour la validation du nettoyage". S.T.P Pharma Pratiques 10 (5) 270-273 2000.

[13] A3P revue "La Vague" – Frédéric Laban – "Nettoyage des salles propres, faut il valider ou non ? Quels sont les points clés des GMPs ?" – janvier 2006

[14] http://a3p.org/index.php/articles-techniques-et-scientifiques/1154-cahier-pratique-

strat%C3%A9gie-de-validation-des-proc%C3%A9d%C3%A9s-de-nettoyage-des-%C3%A9quipements-de-production-en-industrie-pharmaceutique-la-vague-38.html

(consulted the 27/07/2016) [15] Fourman & Mullen