cppsynd.comcppsynd.com/.../2016/03/cleaning-validation-protocol.docx · web viewbased on...

Title: Cleaning ValidationProtocol for

---------------------------------Line

Table of Contents

No. Subject Page

1 Objective 4

2 Scope 4

3 Description of Equipment and Product 4

4 Responsibility 6

5 Description of the Cleaning Process 6

6 Description of the Sampling Process 7

7 Cleansing agents 7

8 Worst Case Determination 10

9 Determination of Acceptable limits for products 12

10 Concise of Acceptance Limit for Worst Case 30

11 Microbiology 31

12 Training Record Verification 34

13 Verification of Documents 35

14 Reports 35

1. Objective

The objective of this protocol is to demonstrate that the cleaning procedure for ------------------- Machine will successfully and consistently reduce the level of residues to a predetermined level of acceptability, so as to prevent contamination (product or cleaning process related) from adversely affecting the safety and quality of the next product manufactured.

2. Scope

This protocol will cover the cleaning process of the ------------------- Machine for the ampoule products.

3. Description of Equipment and Product

There are ----- sites in ----------------- Pharmaceutical Company.

All of the Equipment and products are mentioned in the following tables.

3.1. Equipment Train

The group of equipment or systems jointly functioning to carry out the production processes for a product “equipment train” in --------- lines is mentioned as the following table:

No.

Loc

atio

n

Inst

rum

ent

Nam

e

Cod

e N

o.

Roo

m

Man

ufac

ture

r

Cou

ntry

1

Lin

e --

-

234567

Lin

e --

---8

9101112

3.2. Products

All of the products that are produced in ------------ lines are mentioned in the following table:--------------- LINE

Uni

t

No. Product name Category Product Dosage(mcg/dose)

Dosageform

Lin

e --

--

1

2

3

4

5

6L

ine

----

--

1

2

3

3.3. Process Description for -------------------- Lines

The -------------------- process involves the following sub processes:

Step Process Description Equipment nameSOP Code No. for Cleaning

of Equipments

1

2

3

4

5

6

4. Responsibility

The following personnel are responsible for the execution of this protocol:No. Cleaning/Testing Done by Recorded on Checked by

1 Equipment Cleaning Machine OperatorEquipment usage/

Cleaning logbook

Production supervisor

2 Visual InspectionHead of Qualification and Validation/QA Expert

Analytical logbook QA Manager

3 Rinse/ Swab SampleMachine operator/ Head of Qualification and Validation/QA Expert/ IPQC

Sampling sheet QA Manager

4 MACHead of Qualification and Validation/ QA Expert/QC analyst

Analytical logbook QA Manager

5 Bio-burden Microbiologist Analytical logbookQA Manager,

QC Manager

6 Rinse recovery challenge testHead of Qualification and Validation/QC analyst

Analytical logbookQA Manager,

QC Manager

5. Description of the Cleaning Process

The ---------------- Machines Code No.: -----------(Line -----) and Code No.: ----------(Line ------) are cleaned manually as per following SOPs:

No. Title Code No.

1

2

3

4

5

6

7

8

9

10

6. Description of the Sampling Process

Sampling Technique

In --------------- Pharmaceutical Company both indirect sampling (rinse test) and direct sampling (swab test) techniques are used to take samples from the ------------------ Machine according to "SOP for Sampling techniques for cleaning validation" Code No.: ----------------------------.

Indirect sampling (rinse test) technique is used to take samples from the -------------------- Machine and Rinse samples are each equal to -------- mL.

Direct sampling (swab test) technique: is used to take samples from the --------------------------- Machine and Surface swab samples each equal to 25 cm2.

The figure of ----------------- Machine is attached to Attachment No.:1, Figure: 1of ----

The figure of Sampling Points of --------------------- Machine are attached to Attachment No.:1, Figure: 2 of ----- to Figure: ------ of -----

Sampling Technique and Difficult to clean parts are mentioned in the following table. Handling of Samples: After the completion of cleaning and collecting samples, the rinse

and swab samples are kept for MAC in the suitable place and transferred to the laboratory for the chemical analysis in a suitable package.

Sampling Technique

Sam

plin

g

Loc

atio

n/ID

Sam

plin

g

Loc

atio

n/N

ame

Sam

plin

g C

rite

ria

Typ

e of

Sa

mpl

e

Sam

ple

Are

a/Q

uant

ity

Reference

Diff

icul

t to

cle

an

(D)

Nor

mal

(N)

Swab

(S)

Rin

se (R

)

Cm

2

mL

1 L1 25 Figure -- of ----

2 L2 25 Figure -- of ----

3 L3 25 Figure -- of ----

4 L4 25 Figure -- of ----

5 L5 25 Figure -- of ----

6 L6 25 Figure -- of ----

7 L7 25 Figure -- of ----

8 L8 25 Figure -- of ----

9 L9 25 Figure -- of ----

10 L10 25 Figure -- of ----

11 L11 25 Figure -- of ----

12 L12 25 Figure -- of ----

13 L13 25 Figure -- of ----

14 L14 25 Figure -- of ----

15 L15 25 Figure -- of ----

16 L16 25 Figure -- of ----

17 L17 25 Figure -- of ----

18 L18 25 Figure -- of ----

19 L19 25 Figure -- of ----

20 L20 25 Figure -- of ----

21 L21 25 Figure -- of ----

22 L22 25 Figure -- of ----

23 L23 25 Figure -- of ----

24 L24 25 Figure -- of ----

25 L25 25 Figure -- of ----

26 L26 25 Figure -- of ----

7. Cleansing agents:The cleansing agent is selected mainly in accordance with the solubility properties of the worst case product. These properties are determined not only by the active pharmaceutical ingredient - possibly present in small quantities - but also by all the substances in the formulation.

Selection of cleansing agent is done according to the following diagram:

In ------------ Pharmaceutical Company, ….. is used as solvent while exchanging products from ………. to ……. for cleaning the equipments.

Cleansing agents are

arenot used during the cleaning process.

8. Worst Case Determination Based on formulation and dosage form, potency, toxicity, and solubility, all products are grouped. The broad groups may then be divided into subgroups according to formulation and process types. After the grouping, the worst-case product is selected from each group. The worst-case product from each group may be the least soluble, the most toxic, or with the highest concentration of active ingredients. However, there is no hard and fast rule for the selection of worst-case products. In some situation, a combination of these parameters may also be used. The worst case related to product is the one containing most insoluble active ingredient, with lowest lethal dose or with highest therapeutic dose.8.1. Line -----

LINE ----

No. Product Name Max Dose Min Dose Potency LD 50 Solubility in

waterDosage Form

123

4

56

Solubility: ------------------LD50: ---------------------Potency: -------------------Min Dose: -----------------------

Worst Cases: ------- > ----------- > ---------------

8.2. Line -------

LINE----- No. Product Name Max

DoseMin Dose Potency LD 50 Solubility in

waterDosage Form

123

Solubility: -------------------------LD50: -------------------------Potency: ------------------- Min Dose: -----------------------

Worst Cases: -------------------------------- > --------------------

9. Determination of Acceptable limits for products

Determining what is an acceptable amount of residue remaining on the equipment is a very heart of cleaning verification. The determination of acceptable carryover limits for pharmaceutical equipment and facilities is actually addressing the question of "what is clean?"Worldwide regulatory guidelines indicate that manufacturers must define their own limits for cleaning validation. Commonly cited limits in literature and in regulatory guideline documents have stated that the surface of equipment must meet the requirements of being:

Visibly clean and Not more than 1/1000th of a therapeutic dose in the next batch, or Not more than 1/10 ppm in the next batch, whichever of the latter two limits is lower

An acceptance criterion of visually clean is exactly what is implies. Contact surface is visually free of residue when inspected by the test executer. The second and third rules are calculated in accordance with below items:

A toxicological level (with the appropriate SFs) A therapeutic dose level (by far the most commonly used) A minimum pharmacologic effect level An allergenic level A NOEL (No Observed Effect Level)

Each of these terms represents an increasing level of safety to the consumer. Different levels may be applied based on therapeutic indication, knowledge of the pharmacological activity of the active ingredients, knowledge of dosage form, knowledge of patient population, knowledge of route of administration risks.The following guideline values applied to the safety factor are shown as below table:

Safety FactorNo. Application Value1 Topical 10-1002 Oral 100-10003 Parental 1000-10000

Specified analytical acceptance criteria for target residues must be established by the manufacturer.It is important in setting acceptance criteria that the limits are scientifically justified.In -------------- Pharmaceutical company the calculation of the limits for the active agent in any subsequently antibiotic product based on dose criterion, toxicity criterion, and 10 ppm criterion for rinse and swab samples used mentioned formulas:

Rinse Samples

Dos

e C

rite

rion

L1= (0.001 )×Min.daily doseof active∈product A (mg )Max .daily doseof product B (mg )

L2( mgcm2 )= L1×Min .Batch¿ subsequent product B (Kg )×106

Shared equipment surface area (cm2 )

L3(mgL )=L2( mgcm2 )× Rinsed surfaced area(c m2)

Rinse volume (L)

Tox

icity

Cri

teri

on L1 (mg )(ADI )=5×10−4×LD 50of A (mgkg )×HumanBody Weight (¿70Kg )

Safty factor (¿1000)

L2 (mg )= ADI (mg )×Min .Batch¿ subsequent product B (Kg )×106

Max.daily doseof product B (mg )

L3(mgL )= L2 (mg )×Rinsed surfaced area(cm2)Rinse volume (L )×Shared equipment surfacearea (cm2 )

10 p

pm C

rite

rion

L2( mgcm2 )=10(mgkg )×Min .Batch¿ subsequent product (Kg )

Shared equipment surfacearea (c m2 )


Rinse volume (L)

Swab Samples

Dos

e C

rite

rion

L1=(0.001 )×Min.daily doseof active∈product A( mgday )

Max .daily doseof product B( mgday )L2( mgcm2 )= L1×Min .Batch¿ subsequent product (Kg )×106

Shared equipment surface area (c m2)

L3 (mg )=L2( mgcm2 )×swabbed surface area (cm2 )

Tox

icity

Cri

teri

on L1 (mg )(ADI )=5×10−4×LD 50of A (mgkg )×HumanBody Weight (¿70Kg )




L3 (mg )=L2 (mg )×swabbed surfacearea (c m2 )Shared equipment surfacearea (cm2 )

10 p

pm

Cri

teri

on L2( mgcm2 )=10(mg

kg)×Min .Batch¿ subsequent product (Kg )

Shared equipment surface area (c m2 )


9.1. Determination of Maximum Allowable Carryover (MACO)The test for MAC of the final rinse is performed as per the HPLC method suitable for each product residue

9.1.1. Rinse Samples

9.1.1.1. Calculation Based on Dose Criterion for Rinse Samples:

L1= (0.001 )×Min.daily doseof active∈product A (mg )Max .daily doseof product B (mg )

L2( mgcm2 )= L1×Min .Batch¿ subsequent product B (kg )×106

Shared equipment surface area (cm2 )


Rinse volume (L)The amount of determined MACOs for --------- lines is shown in below tables:

Line -----

No

Product Name

Min. D

aily Dosage of A

(m

g)

Max. D

aily Dosage of B

(m

g)

Bach size B

(Kg)

Shared equipment

surface area (cm2

)

Rinsed surfaced area

(cm

2)

Rinse V

ol.(ml)

MA

CO

(ppm)

Dosage form

1

2

Line -----

No

Product Name

Min. D

aily Dosage of A

(m

g/day) Max. D

aily Dosage of B

(m

g/day)

Bach size B

(Kg)

Shared equipment

surface area (cm2

)


(cm

2)

Rinse V

ol.(ml)

MA

CO

(ppm)

Dosage form

1

2

Line ------

No

Product Name

Min. D

aily Dosage of A

(m

g/day) Max. D

aily Dosage of B

(m

g/day)

Bach size B

(Kg)

Shared equipment

surface area (cm2

)


(cm

2)

Rinse V

ol.(ml)

MA

CO

(ppm)

Dosage form

1

2

3

4

5

6

Line ---

No

Product Name

Min. D

aily Dosage of A

(m

g/day) Max. D

aily Dosage of B

(m

g/day)

Bach size B

(Kg)

Shared equipment

surface area (cm2

)


(cm

2)

Rinse V

ol.(ml)

MA

CO

(ppm)

Dosage form

1

2

3

4

5

6

9.1.1.2. Calculation Based on Toxicity Criterion for Rinse Samples:

L1 (mg )(ADI )=5×10−4×LD 50of A (mgkg )×HumanBody Weight (¿70Kg )




L3(mgL )= L2 (mg )×Rinsed surfaced area(cm2)Rinse volume (L )×Shared equipment surfacearea (cm2 )

Line -----

No

Product Name AD

I

MinBatchBach¿¿

Max. D

aily Dosage of B

(m

g/day)


(cm

2)

Rinse V

ol.(ml)

Shared equipment

surface area (cm2

)

MA

CO

(ppm)

Dosage form

1

2

Line -----

No

Product Name AD

I

MinBatchBach¿¿M

ax. Daily D

osage of B

(mg/day)


(cm

2)

Rinse V

ol.(ml)

Shared equipment

surface area (cm2

)

MA

CO

(ppm)

Dosage form

1

2

Line -----N

o

Product Name AD

I

MinBatchBach¿¿

Max. D

aily Dosage of B

(m

g/day)


(cm

2)

Rinse V

ol.(ml)

Shared equipment

surface area (cm2

)

MA

CO

(ppm)

Dosage form

1

2

3

4

5

6

9.1.1.3. Calculation Based on 10 ppm Criterion for Rinse Samples:

L2( mgcm2 )=10(mgkg )×Min .Batch¿ subsequent product (Kg )



Rinse volume (L)

Line ----

No Product Name

Bach size B

(Kg)

Shared Equipm

ent Surface area (cm

2)

Rinsed Surfaced

area (cm

2)

Rinse V

ol.(ml)

MA

CO

(ppm)

Dosage form1

2

Line ----

No Product Name

Bach size B

(Kg)

Shared Equipm


2)

Rinsed Surfaced

area (cm

2)

Rinse V

ol.(ml)

MA

CO

(ppm)

Dosage form1

2

9.1.2. Swab Samples

9.1.2.1. Calculation Based on Dose Criterion for Swab Samples:

L1=(0.001 )×Min.daily doseof active∈product A( mgday )

Max .daily doseof product B( mgday )L2( mgcm2 )= L1×Min .Batch¿ subsequent product (Kg )×106

Shared equipment surfacearea (c m2)


Line ---

No

Product Name

Min. D

aily Dosage of A

(m

g)

Max. D

aily Dosage of B

(m

g)

Bach size B

(Kg)

Shared equipment

surface area (cm2

)

Swabbed surfaced area

(cm

2)

MA

CO

(mg)

Dosage form

1

2

Line ---

No

Product Name

Min. D

aily Dosage of A

(m

g/day) Max. D

aily Dosage of B

(m

g/day)

Bach size B

(Kg)

Shared equipment

surface area (cm2

)


(cm

2)

MA

CO

(mg)

Dosage form

1

2

9.1.2.2. Calculation Based on Toxicity Criterion for Swab Samples

L1 (mg )(ADI )=5×10−4×LD 50of A (mgkg )×HumanBody Weight (¿70Kg )




L3 (mg )=L2 (mg )×swabbed surfacearea (c m2 )Shared equipment surfacearea (cm2 )

Line -----

No

Product Name AD

I

MinBatchBach¿¿

Max. D

aily Dosage of B

(m

g/day) Swabbed surfaced area

(cm

2)

Shared equipment

surface area (cm2

)

MA

CO

(mg)

Dosage form

1

2

Line ------

No

Product Name AD

I

MinBatchBach¿¿

Max. D

aily Dosage of B

(m

g/day)


(cm

2)

Shared equipment

surface area (cm2

)

MA

CO

(mg)

Dosage form

1

2

9.1.2.3. Calculation Based on 10 ppm Criterion for Swab Samples:

L2( mgcm2 )=10(mg

kg)×Min .Batch¿ subsequent product (Kg )



Line -----

No Product Name

Bach size B

(Kg)

Shared Equipm


2)

Swabbed surface

area (cm

2)

MA

CO

(mg)

Dosage form1

2

Line ------

No Product Name

Bach size B

(Kg)

Shared Equipm


2)

Swabbed surface

area (cm

2)

MA

CO

(mg)

Dosage form1

2

10. Concise of Acceptance Limit for Worst Case

No. Line -----

Rinse limits (ppm) Swab limits(mg/swab area)

Dose

criterion

Toxicity

criterion

10 ppm

criterion

Dose

criterion

Toxicity

criterion

10 ppm

criterio

n

1

2

No. Line ------

Rinse limits (ppm) Swab limits(mg/swab area)

Dose

criterion

Toxicity

criterion

10 ppm

criterion

Dose

criterion

Toxicity

criterion

10 ppm

criterion

1

2

11. MicrobiologyThe need to include measure to prevent microbial growth and remove contaminate ion where it has occurred should be considered.There should be documented evidence to indicate that routine cleaning and storage of equipment does not allow microbial proliferation.The period and conditions for storage of unclean equipment before cleaning and the time between cleaning and equipment reuse, should from part of cleaning procedures. Equipment should be stored in a dry condition after cleaning. Stagnant water should not be allowed to remain in equipment after cleaning.Control of the bioburden through adequate cleaning and appropriate storage of equipment is important to ensure that subsequent sterilization or sanitization procedure achieve the necessary assurance of sterility, and the control of pyrogen in Non-sterile processing. Equipment sterilization processes may not be adequate to achieve significant inactivation or removal of pyrogen.

11.1. Determination of the microbial statusChecking the microbial status of product contact surfaces can be carried out as part of the cleaning validation, as long as this is not already part of hygiene monitoring.For the determination of limits, the "Supplementary and reviewed guidelines for the manufacture

Of Non sterile medicinal products" in the appendix of EU GMP Guideline can be used. Limits (CFU/plate) for cleanroom classes A to D are specified there, but details are missing about whether they concern personal or surfaces. Because limits for the microbial status of the hand are also specified, it can be assumed that the requirements refer to the surfaces. The values given in this guideline were graded as guideline values or recommended limits which should be reached on average for a larger number of measurements. This only concerns guideline values for Non-sterile production (cleanroom grades A-D). Data about the microbiological status of surfaces in area with requirements E and F (GMP area) are not included in the EU Guideline.

Limits for the microbial status of product contact surfaces

Grade EU GMP Guide Annex 1Contact plates d = 55 mm (CFU/plate)

Proposal for implementationTable/machine (CFU/25 cm2)

A < 1G: < 1W: 2A: 3

B 5G: 5W: 2A: 5

C 25G: 25W: 25A: 50

D 50G: 50W: 100A: 200

G: guideline value (mean value from 10 values in sequence)W: alert limitA: action limit The guideline value of 50 CFU/plate specified for product contact surfaces in area of cleanroom grade D can also be used for product surfaces in the GMP area.

According to experience, it is not a problem to keep this value for freshly-cleaned equipment surfaces presuming correct and hygienic execution of cleaning and drying.

11.2. Testing for Microbiological Contaminations

11.2.1. Sampling instructionsThe sampling methods used for cleaning validation are the typical procedures use by microbiological laboratories . This method include swab sampling with desorption and a pour plate or spread plate count. These methods are "approved" microbiological laboratory method and no additional "method validation" is required. All of the procedures are mentioned in SOP for Sampling techniques for cleaning validation Code No.: ----------------

11.2.2. Sampling recoverySampling recovery (Bioburden recovery) from surface as a general rule for process equipment cleaning validation is not done. Recovery studies as they are typically done for chemical residues are difficult to perform for microbial residues. Part of the reason for this is the variability of

microbiological enumeration. For example, USP <1111> specifies that a limit of 102 CFU means less than 200 CFU.

11.2.3. Acceptance criteria According to GMP manual (Table of previous page)(GMP Manual, Good Manufacturing Practice and Implementation, Sampling Plan, Part 8.F, Dr. Doric Borchet, Dr. Ralph Gomez/Update 08,2010).

The pharmaceutical company's rationale for selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable."

Acceptance criteria and limit calculation

1

Calculation of active pharmaceutical ingredient residues Dose criterion ppm criterion Selection of the appropriate acceptance criteria Calculation of the acceptable residue in a sample Visual criterion (visually clean)

2 Calculation of cleansing agent residues3 Determination of the microbial status

Storage condition of clean surface & equipment Storage condition of surface & equipment was in accordance with cleanroom condition for manufacturing of finished product in antibiotic manufacturing section.

11.2.4. Holding TimeThe concepts of "clean-hold time" and "dirty hold time” have been part of cleaning validation since its inception. Clean hold time is generally considered to be the time between the completion of cleaning and the initially soiled, but more often is defined as the time between the end of manufacturing and the beginning of the cleaning process. Intuitively, it make sense to be concerned about both hold times. Dirty equipment is harder to clean the longer the hold time; and clean equipment has a greater chance of becoming soiled as hold time increases.

11.2.4.1. Dirty Hold Time The concern with dirty-hold time is that holding soiled equipment makes it more difficult to remove pharmaceutical soil and allows biological contamination to proliferate. After process has been performed, the equipment can only be left in a dirty state for a maximum identified time before it must be cleaned. Dirty hold time is defined when the equipment soiled till the beginning of the cleaning process. if DHT is defined 72 hours, it means soiled equipments should not hold more than 72 hours and if it happens, cleaning procedure will be different and effectives has to approved. Note: in ------------ pharmaceutical company, DHT is defined ------------ hours, before mentioned time, dirty equipments must be cleaned.

11.2.4.2. Clean Hold TimeAfter cleaning has been performed, the equipment and piping will only be considered clean for a maximum identified time. If the equipment is left unused for more than this time, it must be partially cleaned again prior to use. Standard operation procedure (SOP) of partial cleaning will be attached to this protocol. For long time storage of equipment after full cleaning, cover equipments with plastic covers to protect them against dust and pollution. Daily microbiological test have to be done for assessment of clean hold time after cleaning of three trial batches. Up to that time microbiological test result meets the specification, reusing of equipments has no restriction. When out of specification results appear, clean hold time is finished. Test results for clean hold time assessment for each section is attached the report.

11.2.5. Results of Microbiological testsResults of Microbiological tests are according to "Format for Cleaning Validation Report for ------------------------- Machine", Code No.: -----------------------.

12. Training Record Verification

In ------------------ Pharmaceutical Company all of the personnel who take part in cleaning process are trained according to the Training SOP, Code No.:---------------------and "Major Cleaning of ---------------------- Machine while exchanging products" SOP: Code No.: ----------------------

The following staff found trained on cleaning of the equipment and The analyst trained on standard test methods according to USP -------.

No. Line Dep. Name Sign. Date

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

13. Verification of Documents

In --------------------- Pharmaceutical Company, all of the SOPs are according to the master list Code No.:--------------------

14. Reports

Visual Inspection, Rinse analysis reports, Swab analysis reports, Reference Method, Recovery Studies, Validation Assessment, Observation and corrective actions, Summary, Final cleaning validation report and deviation reports are describes in Cleaning Validation Report :Code No.: ------------------, -----------------------, -----------------,