Summary of Cleaning Validation

 

Corporate

STANDARD OPERATING PROCEDURE DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

PURPOSE 

 

EFFECTIVE DATE

12-Jun-2018

:

The objective of cleaning validation is to prove that the equipment / accessories cleaning procedure can consistently clean the previous product, cleaning agent, microbial residues solvent / solution, odour and colour to an acceptable level, to prevent possible contamination and cross contamination in subsequent product. To describe the methodology for assessment of product for cleaning validation introduced in facility. To establish conditions for Matrixing products or equipment.

SCOPE

:

 Applicable to cleaning procedures of equipment and accessories used in manufacturing  Applicable manufacturing of pharmaceutical pharmaceu tical products. RESPONSIBILITY

:

Production: Form a part of the validation. Carrying out cleaning of equipment as per established cleaning procedure.  

Quality Control: Form a part of the validation. To provide the cleaned accessories for sampling such as rinse sample glass bottle, test tubes, Texwipe swab stick, Nylon membrane filter etc. Ensure availability availability of validated analytical methods methods for measurement of product in swabs and rinses and measurement of solvent in the rinses (wherever applicable).  Analyse the cleaning cleaning validation validation samples as as per TI sheet.  

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Engineering: Form a part of validation. To provide utility services during validation. To provide the surface area of equipment. equipment.  

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Quality Assurance: Assurance: Form a part of validation. Preparation of validation master plan for cleaning validation. Establishment Establishme nt of worst case products. Collection of validation samples as per approved sampling plan of equipment. Performing cleaning validation as per approved validation protocol and recording the same.  Approval of the cleaning cleaning validation validation report. 

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Unit Head: Acknowle Head: Acknowledgement dgement of cleaning cleaning validation validation activities and cleaning cleaning validation validation report.

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

DEFINITION

:

EFFECTIVE DATE

12-Jun-2018

Cleaning Validation Cleaning Validation :  A documented evidence that a cleaning procedure is consistent in reducing product residue and removal of cleaning agents, bioburden, flavour, colour (if applicable) from equipment and accessories within the limits of acceptance. Grouping Strategy Grouping Strategy::  A strategy for establishi establishing ng similar cleaning processes, usually based on similar  products or similar equipment, and to validate the cleaning process based primarily on validation data for a representative of the group. Wor Worst st Case: Caselimits :  A process condition or set ofand process conditionswithin encompassing encompassi ng thepose upper lower  processing for operating parameters circumstances SOPs which theand greatest chance chan ce of product product or process process failure when compared compared to ideal ideal conditio conditions. ns. Such condition conditions s do not necessarily include product or process failure. Worst case product : The product selected from a group of products that present the greatest risk of  carry over contamination to other products made in the same equipment by virtue either of its poor  solubility, solubili ty, potency, toxicity or a combination of these factors. Acceptance criteria : To demonstrate during Acceptance during validation that the cleaning cleaning procedure, procedure, routinely employed for a piece of equipment, limits potential carryover to an acceptable level. That limit established must be calculated based on sound scientific rationale. Revalidation: The repeat of initial validation either after changes or periodically to provide assurance that the changes done / time do not affect the cleaning effectiveness. LD50  : The 50% lethal dose of the target residue in an animal, typically in mg / kg of body weight (by the appropriate appropria te route of administration) administration) PDE : The PDE represents a substance specific dose that is unlikely to cause an adverse effect if an individual individu al is exposed at or below this dose every day for a lifetime. LOAEL: The dose at which a significant adverse effect is first observed is the Lowest-ObservedLOAEL:  Adverse -Effect-Level -Effect-Level (LOAEL). NOAEL: No Observed Adverse Effect Level is the highest tested dose at which no “critical” effect is NOAEL: observed. STV : Safe Threshold Value is the toxicologically toxicologically derived health based acceptance limit.

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

1.0

EFFECTIVE DATE

12-Jun-2018

HEALTH, SAFETY AND ENVIRONMENT : Depending on the product, appropriate safety apparel shall be worn during cleaning of equipment.

2.1

PROCEDURE :

2. 2.2 2

Ensu Ensure re th tha at the the pre prere requ quis isit ites es for for c cle lean anin ing g vali valida dati tion on as li list sted ed belo below w are are avai availa labl ble: e:

2.2.1

Validation Validatio n Master Plan defining the programme for cleaning validation. validation.

2.2.2

Cleaning Validation Protocol, “Prerequisite checklist for cleaning validation” 1035-G0038/A13 and Validation Report.

2.2.3

Validated analytical analytical method for measurement measurement of product in the rinses.

2.2.4

Validated analytical analytical method for measurement of product in the swabs.

2.2.5

Validated analytical method for measurement measurement of of cleaning agent in in the rinses/swabs rinses/swabs (if (if applicable).

2.2.6

Validated analytical method for measurement of solvent in the rinses (wherever applicable). applicable).

Note :

The efficiency of sampling recovery of API by the analytical method shall be assessed.

2.2.7

Validated microbiological method for measurement of bioburden on the equipment.

2.2.8

Standard Operating Procedures detailing the cleaning process for various parts / pieces of  equipment.

2.2.9

 Approved sampling plan (for both chemical and microbiological microbiological sampling) taking the complexity and design of the equipment into consideration.

2.2.10

 Approved surface area calculation calculation for equipment.(Ba equipment.(Basic sic information may be taken from equipmentt manufacturer) equipmen

2.2.11

 Approved swab swab locations for equipment’s. equipment’s.

2.3 2.3

Ensu Ensure re th that at the the prod produc uct, t, proc proces ess s and and equ equip ipme ment nt fo forr whi which ch th the e vali valida dati tion on is plan planne ned d are are vali valid d according to a worst case concept.

2. 2.4 4

Ti Time me fr fram ames es for for s sto tora rage ge of uncl unclea ean ne equ quip ipme ment nt fo forr c cle lean anin ing g sha shall ll be esta establ blis ishe hed. d.

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

Note : 1. Three validation exercises shall be carried on equipment for establishment of the time frame of the Uncleaned Uncleaned equipment. equipment. Selection Selection of the worst worst case equipment equipment and and worst case product shall be justified based on logic and scientific rationale. For non-worst case products, products, risk assessment / coupon stud study y shall be performed to evaluate need of subjecting each product for DHT. 2. Swab sampling for hold time study of uncleaned equipment to be performed for different location for different time intervals. 2. 2.5 5

Clea Clean n the the equ equip ipme ment nt as as per per rres espe pect ctiv ive e Stan Standa dard rd O Ope pera rati ting ng Proc Proced edur ure e a ava vail ilab able le at at the the uni unitt level ensuring the following:

2.5.1

Concentration of the specific cleaning agent, cleaning agent quantity, scrubbing time, water  quality, volume of rinse solution required for cleaning is established.

2.5.2

If hot water is used, the temperature of water shall be established.

2.5.3

The number of cleaning cycles to be performed shall be established if a “Clean In Place” system is used.

2.6

As pe per tth he sa sampl mpling plan, coll lle ect the the ri rinse ses s / sw swabs ffro rom m th the eq equip uipmen ment.

Note :

1. The rinse samples collected shall represent the entire rinse volume. 2. During cleaning validation, while cleaning the equipment as per respective Standard Operating Procedure available available at the t he unit if the cleaning parameters are in range then, lower limit value mentioned in equipment equipment cleaning procedure to be considered.

2. 2.7 7

With Withdr draw aw abou aboutt 100 100 ml aliq aliquo uott pe perr acti active ve ing ingre redi dien entt fr fro om the the fina finall ri rins nse e for for meas measur ure ement ment of  of  active ingredient and about 50 ml aliquot from final rinse for measurement of cleaning agent as per Standard Operating Procedure.

2. 2.8 8

With Withdr draw awal al of ri rins nse e sam sampl ples es for for m mea easu sure reme ment nt of co cont nten entt at ever every y sta stage ge is not not requ requir ired ed fo for  r  established establishe d cleaning procedure procedure of of equipment’s. equipment’s. Sampling to be done only from the final rinse / sample rinse and given to QC for measurement, however rinse at each stage to be analysed during the cleaning SOP developmental stage.

2.9 2.9

With Withdr draw aw ab abou outt 50 50 ml ml aliq aliquo uots ts fr from om the the fina finall ri rins nse e / samp sample le rins rinse e for for me meas asur urem emen entt of of s sol olve vent nt / solution, if used for cleaning.

2. 2.10 10

Send Send 100 100 ml ml blan blank k of fi fina nall ri rins nse e (pot (potab able le w wat ater er / pur purif ifie ied d wate waterr / wate waterr for for inje inject ctio ion) n) alo along ng with rinse samples.

2.11 2.11

Swab Swab in indi divi vidu dual ally ly vari variou ous s p par arts ts of of the the e equ quip ipme ment nt per per acti active ve ingr ingred edie ient nt aft after er cle clean anin ing g the the parts as detailed in the sampling plan as per Standard Operating Procedure.

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

Note :

Selection of swabbing sites shall be hard to clean and difficult to sanitise sites. Refer  individual sampling plan for parts to be swabbed.

2.12 2.12

The The cl clea eani ning ng of of th the e equ equip ipme ment nt’s ’s don done e in all all the the tthr hree ee val valid idat atio ion n runs runs sha shall ll be be done done pre prefe fera rabl bly y by different operators to verify the ruggedness of the cleaning procedure.

2.1 .13 3

Labe abellin ing g an and sto stora rag ge o off c clleanin ning va validati dation on sa samp mplles.

2.13.1

Label each rinse/ swab sample appropriately. Refer annexure 1035-G-0038/A1 for specimen label.

2.13.2

Sample storage: The sample shall be stored in a proper container / bottle with proper  labelling labellin g so as to prevent contamination contamination or alteration during storage.

Note : Cleaning Cleaning Validation sample analysis shall be initiated within 24 hours after receipt of  cleaning validation sample until and unless solution stability studies are available to justify the analysis period 2.14

Visual verification:

2.14.1

Visually inspect the final rinse / sample rinse of each part of equipment to ensure that it is clear and colourless.

2.14.2

Visually inspect inspect the equipment and its parts to ensure that it is clean.

2.14.3

Usage of torches, mirrors etc. can be done for verification of cleanliness visually wherever  required.

2.14.4

Officers / operators operators assessing assessing visual cleanliness cleanliness shall be be trained for observing and identifying drug substance residue at low level concentration. Training can be provided by subjecting officers to review and identify drug substance residue at lower level which is generated by spotting solutions of lower concentrations on stainless steel plates performed during recovery studies conducted by laboratory for validation of analytical method.

2.15

Odour verification criteria:

2.15.1

In formulations formulations where flavours are used, ensure that final rinse / sample sample rinse and equipmentt are free from the characteristic odour of flavours used in the previous product. equipmen

2.16 2.16

Wate Wa terr for for inje inject ctio n / Dis Disti till lled ed wat water er sha shall ll be use used d as as/ the th e las lasttshall ri rins nse ebe for foused r equi equipm pmen entt to be be uti utili lise sed d in production ofion sterile products and purified water steam for  equipmentt in case of non sterile products. For aerosols, alcohol / purified water can be used equipmen for final rinse followed by propellant rinse. Selection of solvent for swabs shall be based on Active ingredient solubility.

2.16.1

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

2.17 2.17

EFFECTIVE DATE

12-Jun-2018

Meas Measur ure e th the e cont conten entt of acti active ve ingr ingred edie ient nt in ri rins nses es / swab swabs s as per per th the e Qual Qualit ity y Cont Contro roll method. Al Also so conf confir irm m if the the pres presen ence ce of cle clean anin ing g agen agentt used used,, iin n the the fina finall rrin inse se /s /sam ampl ple e rin rinse se/s /swa wab b (if  (if  applicable) is within acceptance level.

2.18 2.18

2.19 2.19

For For so solv lven ents ts oth other er tha than n wat water er a and nd vol volat atil ile e orga organi nic c solv solven ents ts,, when when use used d for for clea cleani ning ng,, resi residu dues es of solvents shall be checked in addition to API and cleaning agent.

2.20 2.20

Base Based d on on the the anal analys ysis is,, calc calcul ulat ate e the the amo amoun untt of resi residu due e pre prese sent nt in in eac each h rin rinse se / swab swab and and measure probable contamination in the next product.

2.21

Microbiological aspects of cleaning validation:

2.21.1

Bioburden study of equipment shall be performed, after cleaning / sanitisation, to ensure microbiological microbiolo gical cleanliness. cleanliness.

2.21.2

No stagnant water shall be allowed to remain in the equipment subsequent to cleaning operations.

2.21.3

Equipment shall be dried before storage by an appropriate method of drying as per SOP or  allow all the water to drain from the equipment and its parts.

2. 2.22 22

Ti Time me fr fram ames es for for s sto tora rage ge of cl clea eane ned de equ quip ipme ment nt sh shal alll b be e est estab abli lish shed ed..

Note :

Three validation exercises exercises can be carried on equipment for establishment of the time frame of the cleaned equipment. Selection of the equipment and number of run shall be justified based on logic and scientific rationale.

2.23

Acceptance Criteria:

2.23.1

The limits for acceptance criteria are based on therapeutic dose, batch size, LD surface area.

2.23.2

The established limit ensures that product residue meets the following criteria:

  and

50

Dose criterion: Not more than 0.001 part of the minimum therapeutic dose of the previous  Active substance shall appear appear in the maximum maximum daily dose of the next next considered product. product.

2.23.2.1

Scientific rationale for the above statement is: 



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Pharmaceuticals are often considered to be non active at 0.1 part of their normally prescribed dosage (1/10th). The second is a safety factor of 10 (1/10th of the above). The third factor of 10 is included to make the cleaning procedure procedure robust and to overcome variations due to personnel and sampling methodology (1/10th of the above).

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

10 ppm criterion: Not more than 10ppm of the previous product shall appear in a subsequently produced product. Scientific rationale for the above statement is:

2.23.2.2

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Not more than 10ppm of any product will appear in another product. Scientific rationale for above is based on regulations for food industry which provides for  maximum permissible limit of certain levels of hazardous substances considered as acceptable in products that enter human food chain. PDE criterion: To consider the Health based limits.

2.23.2.3

Scientific rationale for the above statement is: 

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

2.23.2.4

PDE (permitted daily exposure) is toxicologically derived and not simply on dosage. The PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an individuall is exposed at or below this dose every day for a lifetime. individua Determination of a PDE involves (i) hazard identification by reviewing all relevant data, (ii) identification of “critical effects”, (iii) no-observed-adverse-effect-level (NOAEL) of the findings that are considered to be critical effects, and (iv) use of several adjustment factors to account for various uncertainties. uncertainties. For details of PDE criterion defined by the toxicologist refer SOP 1035-G-0209. 1035-G-0209. Visual verification: No quantity of residue shall be visible on the equipment after cleaning procedure is performed. The most stringent limit of acceptance that would emerge from Dose criterion and 10ppm criterion and PDE criterion shall be applied during validation exercise along with visual Verification. Swab recovery factor shall be considered for calculation during validation.

2.2 .23 3.3 2.23.3.1

Pro roc cedur dure Fo For Rin Rins se and and Swab wab Ana Analy lys sis :  Analyse the rinse and swab samples in laboratory using validated analytical method. Apply recovery factor (obtained from validation study) for calculating the content if the same is found less than 100 %. If recovery is observed more than 100 %, do not apply factor for  calculation. Observed value X 100 Results = % Recovery

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

For example, If the % recovery of the method is 79 % and result obtained is 2.0 ppm, then apply recovery factor as follows: Content Cont ent (ppm) (ppm ) = 2.0 x 100 = 2.53 ppm. 79 Limit of detection shall be reported in the Technical Information sheet for cleaning validation.. validation 2.23.4

 Acceptance forspecified Residuallimit. solvents: Results obtained for residual solvent shall be less than 1/10th ofcriteria the ICH I CH

2.23.5

Cleaning agents: agents: Cleaning agents used shall be easily easily removable. The acceptance criteria for cleaning agent shall be calculated for each equipment by determining the carryover to next product through Safe Threshold Value derived from PDE criteria similar to that used for   API, for every equipment. equipment. The cleaning agent shall not be more than this calculated acceptance criteria.

Note:

 Acceptance criteria for cleaning agent can be calculated by using PDE value. STV (Acceptance criteria) can be derived by using below mentioned formula. Formula to get safe threshold value (STV) for Rinse: PDE PD EX K X A = L B Where,

Jppm of cleaning agent

PDE J L

= Pe Permitted daily exposure = Max Maxiimum mum numbe mber of dos dosag age e units nits of ne next co con nsi sid dered red produ roduc ct ta take ken n / day ay.. = Surf Surfa ace area rea of equ equiipmen ment’s t’s com commo mon n fo for bot both h th the e pr pro oduct cts s (p (previ revio ous and and considered next product) K = Nu Number of do dosage units pe per ba batch of ne next c co onsidered product  A = Area of specific equipment equipment sampled B = Quantity of final rinse / sample rinse in kg or Litre Note : For Veterinary and topical products where safe threshold value (STV) cannot be calculated, in such cases 10 ppm criteria shall be used. 2.23.6 2.23.7

Total productforcontact surface area shall criteria. include the area of major / minor equipment and accessories calculation of acceptance  Analytical method validation of residue estimation methods for the products selected as worst cases shall be performed prior to analysis of cleaning validation samples.

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

2.23.8

During analytical cleaning method validation, recovery study shall be applied on the worst case active, whenever we have products with two or more actives.

2.23.9

Quality Control Laboratory shall provide result of samples analysed along with limit of  detection value (for rinse as well as swab technique) of analytical method used to analyse cleaning validation samples.

2.23.10

Quality Assurance shall verify the compliance of all the results obtained for final rinse and swabs which shall be less than the acceptance criteria established.

2.23.11

If results reported samples laboratory are belowagainst detection limit (Below LOD), detection limit shallfor beswab considered as by residue and evaluated acceptance criteria for  compliance. complianc e. Detection limit of swab shall be less than the acceptance criteria.

2.23.12

 Any failure to meet the acceptance criteria must be investigated investigated to determine the cause and appropriate actions (for example, re analysis) shall be taken as necessary.

2.23.13

In case the Acceptance Criteria is found less than the Limit of Detection (LOD) of the analytical method, following actions to be initiated :





 Analytical method to be optimized to achieve lower limit of detection by slight modification such as increasing injection volume in case of chromatographic method like HPLC/ GC/ UPLC etc or increasing cell length in case of UV methods from 1 cm to 4 / 5 cm path length cell. If above modification does not provide limit of detection lower than acceptance criteria established, new method to be developed which can achieve required lower detection concentration.. In case of modification, concentration modification, method shall be re validated. More surface area can be considered for swabbing (For example, 16 sq. inches). In case of  rinse sampling, volume of sample rinse can be decreased, resulting into increase in the residue concentration concentration and hence can be easily detected. If swabbing area or rinse volume is modified, acceptance criteria also need to be corrected and re calculated with revised area or revised rinse volume.

Note :

Swab and Rinse sampling shall be done for routine cleaning validation. However, swab sampling shall be considered as the primary criteria for cleaning validation. If the results of  rinse sampling sampling considering considering the final final rinse volume volume and the Limit Limit of Detection Detection for rinse samples are observed to be more than the acceptance criteria, then only swab sampling shall be done and the cleaning validation exercise shall be concluded based on results of  the swab sampling.

2.23.14

If the cleaning procedure consistently consistently reduces the contaminants to a level within the limits of  acceptance criteria, then the procedure being followed for cleaning can be regarded as validated.

2.24

Calculation of the amount of residue present in rinse and swab:

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

2.24.1

Rinse Method:

2.24.1.1

Content of target residue (Active substance and cleaning agent) in the rinse is reported in ppm by Quality Control.

2.24.1.2

Compare the results obtained from QC in ppm with limits of acceptance criteria for rinse collected from the part of equipment. equipment.

2.24.2

Swab Method:

2.24.2.1

Content / Residue of previous product is reported in microgram per 4 inch by QC.

2.24.2.2

It is to be converted into milligram by dividing the residue in µg reported by QC by 1000. This is the possible contamination contamination in next considered product product in mg/4 inch2 Example: Conte Co ntent/ nt/res resid idue ue in in µg /swa /swab b from from resul results ts of of analys analysis is = 10.18 10.18 2 µg/4inch Possible co contaminati tio on in in ne next co considered p prroduct = 10.18mg 1000 = 0.01018 mg/4 inch2.

2.24.2.3

If swabbing area is less than 4 sq. inch then QC shall report the results mg/swab Example: Content/r Con tent/resid esidue ue in in µg /swa /swab b from from results results of analys analysis is = 10.18 10.18 µg/swa µg/swab b

2

If swab is collect collec t from 2.5 sq. inch then =10.18 =10. 18 x 4 sq.  inc in ch Surface area of the part = 10.18 x 4 2.5 = 16.288 µg/4inch2 Contamination in next considered product = 16.288 mg 1000 = 0.01629 mg/4 inch2. Note:1. Note: 1.

In case case of thermolabile thermolabile API, API, for cleaning validation, validation, only only swab swab method shall be followed, followed, as for rinse method, the rinse will be evaporated at high temperature and this can cause degradat degr adation ion of the temperat temperature ure sensitive sensitive API and will affect affect the subsequ subsequent ent analytica analyticall results.

2. For live culture like Lactic Acid Bacillus containing containing products, products, the cleaning validation validation assessment shall be done by “Sterile swabbing” method where the media used for  swabbing shall be Normal saline. In this case, rinse method shall not be followed.

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

2.25

Procedure for Rinse Sampling:

2.25.1

Clean the equipment as per the respective cleaning procedure.

2.25.2

Collect the rinse samples as specified in individual sampling plan.

2.25.3

Rinse sampling shall primarily be used in cases where the surfaces are difficult to reach.

2.25.4

Rinse sampling Rinse sampling shall be done done by using using clean clean bottles bottles toward toward any potential potential contamin contaminant ant carryover.

Note :

1.) Final rinsing of equipment equipment using the cleaning medium shall be carried out as mentioned in the cleaning cleaning SOP. While, sample collection collection shall be performe performed d by using using establis established hed additional cleaning medium (sample rinse) following final rinse. 2.) Established additional cleaning medium (sample rinse) derived after performing the study shall be the minimum possible quantity required to cover the intended part of the equipment to be rinsed and shall be mentioned in the sampling plan.

2.25.5

Type of rinse sampling:

2.25.5.1

Holding type: Collect sample in vessel, swirl and then collect sample.

2.25.5.2

Non approachable approachable piping: Collect samples by passing solution from one end and collect from the other end.

2.25.6

Rinse samples Rinse samples can be collecte collected d using using any type mention mentioned ed above, above, dependin depending g upon the requirement.

2.26

Procedure for Swab Sampling: Preparation: As per the information obtained from the production arrange for the required number of flasks, bottles with screw cap, swab (Membrane filter/ swabstick), forceps / tweezer, hand gloves, nose masks and sampling kit.

Note: 2.26.1

Do not touch the swab with hand. Use tweezers / forceps for swabbing (as applicable). Depending on the product, moisten the swab (Membrane filter/ swabstick) with appropriate solvent. Use hand gloves, nose mask and snood whenever required.

2.26.2

Immediat Imme diately ely after after wetting wetting the membrane membrane filter / swabstick swabstick,, swab swab the specific specific equipment equipment surface as as per the sampling sampling plan. The surface surface area area shall shall be swabbed is 4 square inch. If  the surface area is less than 4 square inch, complete surface area shall be swabbed. Swab sample will be taken after final rinse from equipment surface which is hard to clean. Swab locations shall be determined based upon logic and practical experience. Equipment geometry also shall be considered. Same shall be justified in respective sampling sampling plan.

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

2.26.3

In case of surfaces where 4 square inch measureme measurement nt for swab sampling is not possible like pipes, cavities, groves, mesh etc. Following approach shall be adopted.

2.26.3.1

Swab the surface such that it will cover the maximum possible possible accessible area, for example, in case of pipes, do the swabbing in circular motion from outer edge to inner surface in clockwise direction and from inner surface to outer edge in anti clock wise direction or as per  requirementt ensuring that the maximum area is covered. For calculation, retain the area of 4 requiremen square inches.

2.26.3.2

Wherever of such equipment / components is possible, andinwash same with dismantling known amount of solvent / cleaning solution and determinedismantle the content rinse.the

2.26.4

Stainless steel / Teflon / PVC template shall be used for determining the surface area of the swab, or eye ball method be practiced and validated for each sampling personnel personnel..

2.26.5

Do the swabbing in a “Painting” motion across the surface, first applying the swab in a vertical direction and rotate 90° to horizontal position as shown below in figure 1. 2” 2” R O T A T E

2”

Vertical swabbing

2.26.6

Note:

2.26.7

S W A B

2”

Horizontal swabbing

Transfer the swab using tweezer (as applicable) into the flask/bottles/Test tube and analyse as per the t he validated analytical method. For swab use nylon membrane filter (Pall Gelman Science/Pall Life Science/Membrane Disc Filter) or swabstick (texwipe). Dimension for swab shall be as mentioned in the unit SOP. Before using swabstick (texwipe), ensure that swab recovery data is available. Swab for microbiological testing shall be taken from any one location, generally a site that is difficult to clean and this shall be done by a microbiologist / trained person as per 1035-L0071 and from a different surface than the chemical swabs withdrawn. Ensure that the surface is not wet and at ambient temperature temperature..

Note :

Micro swab sample shall be collected prior to chemical swab sample.

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

2.26.8

 After taking swab, wipe out the part equivalent to which swab is taken with lint free cloth and visually inspect the part for cleanliness for non sterile products and water for injection / distilled water for sterile products as per respective cleaning SOP, (final rinse only) followed by steaming with pure steam.

2.26.9

Recovery of swab technique shall be considered “Good” if it is more than 80% and “Moderate” if it is more than 60%. If it below 60%, investigation investigation of the same shall be done.

2.27

Establishment of worst case product: In order minimise the amount of validation required,There a worst case for validation shall be to used by means of a worst case procedure. shall beapproach documented scientific rationale for the chosen worst cases. Bracketing of products shall be done by grouping of  products manufactured using a particular equipment chain or equipment. equipment.

2.27.1

In Ind div iviidual Eq Equipment Co Concept:

2.27.1.1

 A flow chart showing the product manufactured using the equipment equipment shall be prepared at unit level.

2.27.1.2

Group the products manufactured using each equipment equipment and perform the cleaning validation on worst case products.

2.27.1.3

Batches meant for registration/feasibility shall not be considered as next product for  calculation calculatio n of acceptance criteria.

2.27.1.4

However, for feasibility batch evaluation shall be done as similar to routine product that is one full cleaning validation run as per annexure 1035-G-0038/A6 and 1035-G-0038/A7 and if product taken for feasibility batch is identified as worst case, inline with routine approach cleaning validation on minimum three batches shall be done for the said product (these three runs can be combination of feasibility / registration / commercial) and matrix to be updated with first registration batch. Equipment Ch Chain Concept:

2.27.2 2.27.2.1

 A flow chart exhibiting exhibiting the equipment equipment chain shall shall be prepare prepared. d.

2.27.2.2

The code number of the individual equipment shall be documented, along with their  capacities and surface areas. Total surface area of the equipment chain shall be calculated by adding up all the individual surface areas.

2.27.2.3

Surface area of accessor Surface accessories, ies, if used at any stage shall be accounted accounted in the total surface surface area.

2.27.2.4

If the cleaning procedure of different products differs with respect to different cleaning solvents used, grouping of products shall be done as per that.

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

2.27.2.5

For complete equipment chain along with capacities and surface areas, give the reference chain number. Record the data in Annexure 1035-G-0038/A2.

2. 2.27 27.3 .3

Sele Select ctio ion n of of the the wor worst st cas case e pro produ duct ct/s /s fo forr per perfo form rmin ing g cle clean anin ing g validation is as follows :

2.27.3.1

Worst Case Products on basis of solubility :  Active ingredient ingredient having least solubility in their cleaning solvent are most difficult to clean and possibility of carryover contamination of that ingredient into the next product is maximum. Hence the products having worst solubility profile in their cleaning solvent shall be selected as the worst case product in this criterion. In case where the solubility profile of two or more products is identical, product having the highest strength shall be selected as worst case in tthis his criterion. In case there are two products having same solubility and same strength, then the higher  potent drug (least therapeutic dose) among the two drugs shall be selected as worst case in this criterion. Whenever we have worst case products with two or more actives with different solvents used for cleaning, for both actives study the solubility of each of the actives in both the solvents Interpretation of solubility Solubility

2.27.3.2

Approximate quantities of solvent by volume for 1 part of solute by weight. Less than 1 part.



Very soluble



Freely soluble

From 1 to 10 parts



Soluble

From 10 to 30parts



Sparingly soluble



Slightly Soluble



Very slightly soluble

From 1000 to 10000 parts



Practically insoluble

More than 10000 parts

From 30 to 100 parts From 100 to 1000 parts

Worst Case product on basis of least therapeutic dose (potency): Product having maximum potency poses maximum health hazard if contaminated in other  product. Product having least therapeutic dose is considered to be most potent.

Note: 1)

In case case there there are are two products products having having sa same me po potenc tency y then then one one having having higher higher strength strength shall shall be considered

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

2) In case there are two products having the same potency and same strength, then practically insoluble insoluble product shall be considered as worst case product. Worst Case product on basis of toxicity (least PDE value):

2.27.3.3

LD50  (Toxicity data) for the new drug shall be obtained from authentic source such as drugbank.com,, MSDS, Scientific Journals, etc. and shall be entered in the data bank. Same drugbank.com data bank shall be referred whenever required. Record the NOAEL and PDE value of each drug in annexure 1035-G-0038/A2. Product having lowest PDE value shall be selected as worst in made ‘toxicity’ criterion and inle) annexure 1035-G-0038/A2. report case can be by toxicologist (Ifrecord applicab applicable) as per SOP 1035-G-0209. PDE evaluation In case where the PDE value of two or more products is identical, product having the least solubility shall be selected as worst case in this criterion. In case there are two products having same PDE value and same solubility, solubility, then the higher  potent drug (lowest therapeutic dose) among the two shall be selected as worst case in this criterion. 2.27.4

 

 

   

Perform three cleaning validation studies of the respective equipment, or equipment chain and the product selected as Worst case. Calculate the acceptance criteria by considering following parameters by referring the equipment chain of that product. For Dose criteria: Product having minimum K/J ratio Surface area of equipment common for both the products (previous product and considered considered next product) For 10 ppm Criteria: Minimum batch size in kilograms/ litres of next considered product. Surface area of equipment equipment common for both the products (previous product and considered next product) Record the data in Annexure 1035-G-0038/A2. For PDE criterion: LD 50 / NOAEL / PDE value of product. PDE value considering considering various extrapolating extrapolating factors. f actors. Product having minimum K/J ratio Surface area of equipment equipment common for both the products (previous product and considered next product)

Note:

For new molecules introducing in the facility the PDE value considering NOAEL value shall be obtained from toxicologist as per the SOP 1035-G-0209. In case of Legacy products NOEL shall be considered in place of NOAEL till the PDE value is not available as per the SOP 1035-G-0209. 1035-G-0209.

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

If worst case product is not planned within 3 months and can not be validated then review and validation of the 2nd or subsequent worst case product shall be considered. Record the subsequent worst case product details in Annexure 1035-G-0038/A14. Next product shall be selected for calculation of acceptance criterion based on the minimum batch size and maximum daily dose. Cleaning validation shall be re-run for the first worst case product when it is available. Carryover contamination of a particular amount of product residue of previous product shall be distributed throughout the batch size of the next product. Content of residue of previous product, per dose of next product be highest for a minimum batch sizeproduct. of next product, as the dilution of the residue shall shall be least in a minimum batch size of next Moreover, as the batch size of the next product comes in the numerator of the formula for  calculation of acceptance criteria, the product which has the minimum batch size, shall be considered as the worst case product to make the acceptance criteria stringent. 2.27.4.1

Next product Next product to be selected selected for calculati calculation on of acceptan acceptance ce criterion criterion based on the maximum daily dose of the product and minimum batch size: Risk of health hazard due to carryover contamination in next product is maximum for those products which have maximum number of daily doses. As per day intake of the previous product residue by a patient shall be maximum in case of next product having maximum daily dosage units. Moreover, as batch size of subsequent product is in numerator, maximum daily dose is in the denominator of the formula for calculating acceptance criteria, the product having maximum daily dose, shall be considered as the worst case product as the acceptance criteria will be most stringent in this case. The product having maximum daily dose in the chain shall be considered as “Worst case” product. Maximum daily dosage number to be considered as “J” in Dose criteria calculation. calculation. Based on the above justification product having minimum K/J ratio shall be considered as next product for calculatio calculation. n.

2.27.5

Common surface area of equipment’s used between previous and considered next product shall be considered as “L” in Dose criteria, in PDE Criteria and “T” in 10ppm criteria calculation calculatio n as per Annexure 1035-G-0038/A9. 1035-G-0038/A9.

2. 2.28 28

If a prod produc uctt havi having ng mor more e than than o one ne act activ ive e ingr ingred edie ient nt,, then then vali valida date te the the prod produc uctt for for acti active ve ingredientt which is identified as worst case based on solubility/potency/tox ingredien solubility/potency/toxicity. icity.

2.29 2.29

Base Based d on on all all the the abo above ve,, ‘W ‘WOR ORST ST CAS CASE” E” pro produ duct ct for for cal calcu cula lati ting ng acc accep epta tanc nce e cri crite teri ria a shal shalll be be established.

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

2. 2.30 30

Id Iden enti tify fy and and Rec Recor ord d the the prod produc ucts ts w whi hich ch are are con consi side dere red d as “WO “WORS RST T CASE CASE”” base based d on the the solubility, therapeutic potency, PDE value and the “WORST CASE” product based on batch size in Kg / litres and maximum Daily Dose in Annexure 1035-G-0038/A2.

2.31 2.31

Perf Perfor orm m cle clean anin ing g vali valida dati tion on for for each each equi equipm pmen entt on on th the e prod produc uct/ t/s s deci decide ded d as “WOR “WORST ST CASE” product. Carry out 3 consecutive successful cleaning validation for the product / (s) considered “WORST CASE” product and record in Annexure 1035-G-0038/A3.

2.3 .32 2

Calcu cullat ate e th the lim limiits for for Ac Acce cep ptan tance Crite iteri ria a as as ffo ollo low ws:

Note:1 Note: 1.

For all external use preparations, only 10ppm criteria shall be followed.

2.

For oph ophtha thalmi lmic c prepa preparat ratio ions ns follo followin wing g poin points ts shal shalll be cons conside idered red:: The most stringent limit of acceptance that will emerge from 10 ppm criteria, dose criteria and PDE criteria shall be applied during validation exercise instead of applying only 10ppm criteria, (considering criticality and systemic absorption of ophthalmic product compared to other external formulations). formulations).

a)

The unit unit dose dose of of previo previous us prod product uct shall shall be be consid considere ered d as 0. 0.03 035 5 ml, whi which ch is ocul ocular ar capa capacit city y (average) of human eye and the minimum dose of previous product shall be considered as concentration of API in 0.035ml dose (or single drop volume if it is less than the ocular  capacity & minimum dose recommended is single drop).

b)

Numbe Numberr of of dosa dosage ge units units per per ba batch tch of next next consid considere ered d p prod roduct uct shall shall be calcu calculat lated ed considering considerin g 0.035ml unit dose.

2.32.1

Limits of acceptance criteria for swab:

2.32.1.1

Dose criterion: Formula:  I X K XM= L Where, I J L K M

2.32.1.2

Jmg of previous product / 4 inch2 or 16 inch2

= 0. 0.001 of mi minimum therapeutic dose of previous product in mg. = Max Maxiimum mum numbe mber of dos dosag age e units nits of ne next co con nsi sid dered red produ roduc ct ta take ken n / day ay.. = Surf Surfa ace area rea of equ equiipmen ment’s t’s com commo mon n fo for bot both h th the e pr pro oduct cts s (p (previ revio ous and and considered next product) = Nu Number of do dosage units per ba batch tch of ne next c co onsidered product 2 = 4 or 16 (for reporting results per 4 inch or 16 inch2)

10 ppm Criterion :

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

Formula: RXSXU= Where, R S T U

Tmg of previous product / 4 inch 2 or 16 inch2

= 10 mg acti active ve ingr ingred edie ient nt in prev previo ious us prod produc uctt / kg of next next co cons nsid ider ered ed prod produc uct. t. = Mi Minimu imum Ba Batch tch si size in ki kilogram rams / lilitre tres of of n ne ext consi onsid dered red pro produ duc ct. = Su Surfac rface e are area a of of equ equiipmen ment’s t’s co common fo forr bo both th the e pro prod duct cts s ((p previ revio ous and considered next product) = 4 or 16 (for reporting results per 4 inch2 or 16 inch2)

PDE criterion:

2.32.1.3

Formula to get safe threshold value (STV) : PDE X K X M = J L

mg of previous product / 4 inch 2 or 16 inch2

Where, PDE J L K M 

= Pe Permitted daily exposure = Max Maxiimum mum numbe mber of dos dosag age e units nits of ne next co con nsi sid dered red produ roduc ct ta take ken n / day ay.. = Surf Surfa ace area rea of equ equiipmen ment’s t’s com commo mon n fo for bot both h th the e pr pro oduct cts s (p (previ revio ous and and considered next product) = Nu Number of do dosage units per ba batch tch of ne next c co onsidered product 2 = 4 or 16 (for reporting results per 4 inch or 16 inch2)

The Permitted Daily Exposure (PDE) is determined by following equation: NOAEL X weight adjustment PDE = F1 X F2 X F3 X F4 X F5 The modifying factors are as follows: F1 = A factor to account for extrapolation between speci species es F1 = 5 for extrapolation from rats to humans F1 = 12 for extrapolation extrapolation from mice to humans F1 = 2 for extrapolation from dogs to humans F1 = 2.5 for extrapolation from rabbits to humans F1 = 3 for extrapolation from monkeys to humans F1 = 10 for extrapolation extrapolation from other animals to humans

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

F2 = A factor of 10 to account for variability between between individuals F3 = A variable factor to account for toxicity studies of short-term exposure F3 = 1 for studies that last at least one half lifetime (1 year for rodents or rabbits; 7 years for  cats, dogs and monkeys). F3 = 1 for reproductive studies in which the whole period of organogenesis organogenesis is covered. F3 = 2 for a 6-month study in rodents, or a 3.5-year study in non-rodents. F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents. F3 = 10 for studies of a shorter duration F4 = A factor that may be applied in cases of severe toxicity, e.g., non-genotoxic non-genotoxic carcinogenicity, neurotoxicity neurotoxicity or teratogeni teratogenicity. city. In studies of reproductive toxicity, the following factors are used: F4 = 1 for f or fetal toxicity associated with maternal maternal toxicity F4 = 5 for fetal toxicity without maternal toxicity F4 = 5 for a teratogenic effect with maternal toxicity F4 = 10 for a teratogenic effect without maternal toxicity F5 = A variable factor that may be applied if the no-effect level was not established. When only an LOEL is available, a factor of up to 10 could be used depending on the severity of  the toxicity. Note:

1. If values of individual factors are not available then consider highe highest st value. 2. If the NOEL value is is available, available, F5 factor shall be considered considered as 1. 3. If body weight weight is considered while while calculation calculation of NOEL, then weight adjustment adjustment factor  shall be considered as 1 while calculation of PDE.



For this approach NOEL shall be estimated from the LD 50 value using the following equation:

NOEL =

LD50 X BW MF1

NOEL = No Observable Effect Level LD50 = The 50% lethal lethal dose dose of the the ta target rget residue residue in an an animal animal,, typical typically ly in in mg mg / weight (by the appropriate route of administration) administration) BW = body weight weight of patient taking taking next product product (50 kg) MF1 MF 1 = The The m mod odif ifyi ying ng fac facto torr sele select cted ed shal shalll b be e not not mor more e than than 1000 1000.. For example, If Alprazolam molecule is considered, Toxicity

NOEL

Oral, mouse: LD50=1020 mg/kg.

= 1020 x 50

STV (safe threshold value) :

1000

PDE = 51

=

51

= 0.004

12 x 10 x 10 x 10

kg of body body

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

0.004 X K X M = L Note :1. :1.

EFFECTIVE DATE

12-Jun-2018

Jmg of previous product / 4 inch 2 or 16 inch2

In case case of low low accep acceptance tance crite criteria ria more area can be be conside considered red for for swabbin swabbing g For examp example le  – 16 sq inch and and cleaning method method validatio validation n shall be updated updated accordingly. accordingly.

2.

If NOEL NOEL is not not a ava vail ilab able le then then go for for LOE LOEL. L.

3.

If NOEL/ NOEL/NOAE NOAEL/LO L/LOEL EL valu value e is is no nott avail availabl able e the then nN NOEL OEL shall shall b be e calcul calculated ated based based LD LD 50.

4.

For single drug, LD50  value may be available for more than 1 species, but sensitivity may vary from species to species. Sensitivity is shown in decreasing order as Monkey----------Dog------------Rat--------------Mice. LD50 value of Rat / Mice shall be considered for calculation.

5.

LD50  value differ based on the type of formulations/Route of administration. While doing calculations calculatio ns for f or cleaning validation LD50 value to be selected based on formulations/Route of  administr admi nistratio ation. n. If LD 50  value is not available available for other route route of administration/ formulation formulation then oral route LD 50 shall be considered. If LD50 varies with respect to API supplier then lowest LD 50 value of same species between two suppliers shall be considered.

6.

7.

For new new molecu molecules les intro introduc ducin ing g in the facili facility ty the PDE PDE value value conside considerin ring g NOAE NOAEL L value value shall shall be obtained from toxicologist as per SOP 1035-G-0209.

8.

If the prod produc uctt inform informati ation on for for the next next medici medicinal nal prod product uct to be be manufa manufactu ctured red expr express esses es the the daily dose on a per patient basis rather than on a mg/kg body weight basis, a standard body weight of 50 kg shall be used for human medicinal products. For medicinal products for  veterina veter inary ry use doses are generall generally y expressed expressed on a mg/kg body weight weight basis. In those those instances where this this is not the case, a standard body weight weight of 1 kg shall be assumed assumed as this would represent the lower end of animal body weights.

2.32.2

Limits of acceptance criteria for rinse: The most stringent limits of acceptance criterion of swab that would emerge from dose criterion crite rion,, 10 ppm criterion criterion and PDE criterion criterion,, that acceptanc acceptance e criterion criterion shall shall be used to derive the limits for the acceptance criterion of rinse. Derive the acceptance criterion for rinse by using following formula:

2.32.2.1

Dose criterion: Formula:  I J

X K X A = L B

ppm of previous product

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

Where, I J L K  A B 2.32.2.2

= 0. 0.001 of mi minimum therapeutic dose of previous product in mg. = Max Maxiimum mum numbe mber of dos dosag age e units nits of ne next co con nsi sid dered red produ roduc ct ta take ken n / day ay.. = Surf Surfa ace area rea of equ equiipmen ment’s t’s com commo mon n fo for bot both h th the e pr pro oduct cts s (p (previ revio ous and and considered next product) = Nu Number of do dosage units pe per ba batch of ne next c co onsidered product = Area of specific equipment equipment sampled = Quantity of final rinse/ sample rinse in kg or Litre

10 ppm Criterion :

Formula: RX S X A= T B Where, R S T

2.32.2.3

ppm of previous product

 A

= 10 mg acti active ve ingr ingred edie ient nt in prev previo ious us prod produc uctt / kg of next next co cons nsid ider ered ed prod produc uct. t. = Mi Minimu imum Ba Batch tch si size in ki kilogram rams / lilitre tres of of n ne ext consi onsid dered red pro produ duc ct. = Su Surfac rface e are area a of of equ equiipmen ment’s t’s co common fo forr bo both th the e pro prod duct cts s ((p previ revio ous and considered next product) = Area of specific equipment equipment sampled

B

= Qu Quantity of fifinal rriinse/ sa sample ri rinse in in kg kg or or Li Litre

PDE criterion: Formula to get safe threshold value (STV) : PDE PD EX K X A = L B Where, PDE J L K  A B

2.33 2.33

Jppm previous product

= Pe Permitted daily exposure = Max Maxiimum mum numbe mber of dos dosag age e units nits of ne next co con nsi sid dered red produ roduc ct ta take ken n / day ay.. = Surf Surfa ace area rea of equ equiipmen ment’s t’s com commo mon n fo for bot both h th the e pr pro oduct cts s (p (previ revio ous and and considered next product) = Nu Number of do dosage units pe per ba batch of ne next c co onsidered product = Area of specific equipment equipment sampled = Quantity of final rinse/ sample rinse in kg or Litre

Comp Compar are e the the amou amount nt of res resid idue ue of the the prev previo ious us prod produc uctt aga again inst st resp respec ecti tive ve esta establ blis ishe hed d acceptance criteria for swab and rinse.

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

2. 2.34 34

Reco Record rd obse observ rvat atio ion, n, co conc nclu lusi sion on and and rrec eco ommen mmenda dati tion ons s iin n tthe he repo report rt..

2.35 2.35

Get Get tthe he re repo port rt appr approv oved ed by Head Head Un Unit it Qu Qual alit ity y Ass Assur uran ance ce.. The The rep repor ortt sha shall ll be note noted d by by Uni Unitt Head.

2. 2.36 36

Atta Attach chme ment nts: s: Foll Follow owin ing g sha shall ll be atta attach ched ed to the the val valid idat atio ion n rep repor ort: t:  Approved sampling sampling plan for for the equipment. equipment. Technical information sheet of cleaning validation sample analysis. Prerequisite checklist for cleaning validation

   

Common surface area of equipment

Note:  Approved surface area calculation calculation and swab location of validated equipment equipment shall be available. 2.37 2.37 2.38 2.38

Duri During ng wors worstt case case dete determ rmin inat atio ion, n, ifif the the p pre revi viou ous s pro produ duct ct and and th the e nex nextt prod produc uctt happ happen en to be same, still attributes of the product shall be considered for acceptance criteria calcul calculation. ation. The The m mos ostt s str trin inge gent nt cri crite teri ria a that that woul would d eme emerg rge e fro from m Dos Dose e cri crite teri rion on,, 1 10 0 ppm ppm cr crit iter erio ion n and and PDE PDE criterion shall be applied during validation exercise along with visual verification for both Rinse and Swab.

Note: In case of failure of visual verification for other than new products, a deviation shall be logged to identify if this is an operator failure or the cleaning procedure failure. In case of  operator error, a recleaning can be performed once and same shall be recorded in the area and equipment cleaning log. 2.39 2.39 Note:

Appr Approv oved ed surf surfac ace e area area calc calcul ulat atio ion n of of equ equip ipme ment nt shal shalll be avai availa labl ble e at at uni unit. t. If similar equipment is used repeatedly in a chain, surface area to be considered only once during calculation calculation of the total surface area.

2.40 2.40

When When no nonn-be beta tala lact ctum um ant antib ibio ioti tic c and and non non-s -sex exua uall horm hormon ones es -co -cort rtic icos oste tero roid ids s prod produc ucts ts are are made in same areas and equipment that are used for manufacture of other products that do not require special manufacturing area, the batches to be manufactured on campaign basis to the extent possible. The equipment cleaning rinses and swabs should be subjected to traces analysis prior prior to starting a new production wh which ich should be testable through producti prod uction on records records or alternate alternate shall have a validate validated d cleaning cleaning methodol methodology ogy in use for  periodic monitoring monitoring of traces of previous product.

2. 2.41 41

Duri During ng a camp campai aign gn (pro (produ duct ctio ion n of seve severa rall batc batche hes s of the the same same pro produ duct ct), ), clea cleani ning ng betw betwee een n batches may be reduced. The number of lots of the same product which could be manufactu manu factured red before before a complete complete/full /full cleaning cleaning is done shall be determin determined. ed. If campaign campaign cleaning validation validation is not not performed on worst worst case product, then batch wise wise cleaning cleaning shall be performed.

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

Note :

EFFECTIVE DATE

12-Jun-2018

In case any new product is introduced in facility, Risk assessment to be performed for  evaluation of worst case product for cleaning validation, if the product is identified as worst case, then update the existing matrix for inclusion of new product and perform full cleaning validation on a minimum of three batches as per annexure 1035-G-0038/A6 and annexure 1035-G-0038/A7. If the product is not identified as worst case, then full cleaning validation will be performed for the first batch of the product as per annexure 1035-G-0038/A6 and 1035-G-0038/A7. Based Base d on result result generate generated d from first batch batch validati validation on study; study; risk assessment assessment shall be reviewed to decide need of two more batches for cleaning validation and matrix to be updated accordingly. accordingly. Risk assessment shall be performed as per SOP no. 1035-G-0024, It shall cover the physical characteristics such as viscosity, processes creating sticky or caked on solids, materials reacting with water (cleaning solvent) to form solid or sticky gel like material, etc. (as applicable) and record the t he observations in Annexure 1035-G-0038/A11. Interview the operator for feasibility of cleaning procedure and record the observations in  Annexure 1035-G-0038/A11. 1035-G-0038/A11. Record any unusual observation or deviation occurred during cleaning procedure.

Note: Cleaning validation shall be extended for two more batches if any one of the factor listed in  Annexure 1035-G-0038/A11 1035-G-0038/A11 is is identified. Prepare a summary report by referring annexure 1035-G-0038/A12, to have a comprehens comprehensive review of all the cleaning validation activities whenever new product is introduced inive facility. 2. 2.42 42

Note:

2.43 2.43

If ther there e is an int intro rodu duct ctio ion, n, e eli limi mina nati tion on or or modi modifi fica cati tion on of of any any equi equipm pmen ent, t, or cha chang nge e in next next product considered for calculation, the surface area calculation shall be revised and if the acceptance criteria emerged from the new calculations is more stringent than the existing limit, the cleaning validation results shall be compared with the new limits and if required, revalidation revalidatio n to be done for all worst case products. If justification / supporting data not available, available, cleaning procedure shall be verified each time, until validations of all the worst case products are completed. If one one eq equi uipm pmen entt c cha hain in has has pro produ ducts cts whic which h are are comm common on fo forr anot anothe herr equ equip ipme ment nt chai chain, n, and and if  the surface area of the former is greater than the latter, then validation of worst cases of the former equipment chain will also justify the cleaning validation of the latter, even if the worst case products of both the chains do not match. For example, Aerosol product. This statement can be justified as, if worst case product/s of the worst chain (having maximum surface area) is validated successfully, then the worst case products of any other  chain chai n (lower (lower surface area) area) need not be validate validated d separate separately ly (provid (provided ed product product list of the worst chain includes products of other chains also and cleaning procedure are same for 

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

equipment used in both chain). This is because, the worst product is already considered in the worst chain, and is being validated. For example; Consider Chain 1 having Products A, B, C, D, E and F in its product list, and among which Product A and C are the worst cases. Similarly, Chain 2 has Products B, D, E and F in its product list and among which Product B and E are worst cases. If the surface area of Chain 1 is greater than Chain 2 and if Product A and C are validated in Chain 1, then the cleaning procedure will stand validated in Chain 2 also, even if Product B and arebe notjustified validated Chain 2.product B and E are not validated in Chain 1, but still the This Ecan as in although same cleaning procedure is effective in cleaning of products worse than the above products (Product A and C). Note :

1. If cleaning procedures are different, all products in equipment worst case shall be validated. 2. If cleaning procedure is ineffective then use dedicated equipment.

2.44 2.44

New New or or tran transf sfer erre red d equ equip ipme ment nt mu must st be subj subjec ecte ted d to to a cl clea eani ning ng veri verifi fica cati tion on by vi visu sual al inspection,, traces of cleaning agent and determination inspection determination of the bioload.

2.4 .45 5

For For n ne ew eq equipme pment cl clea ean ning me metho thodol dology gy,, re refer fer CTG CTG-1 -18. 8.

Note : Ensure that consideration is given to non-contact parts like fans of PLC panels and ovens, mixing shafts, heating elements etc. during performance qualification of equipment and preparation of standard procedures for cleaning of equipment. 2.46 2.46

Regu Regula larr vali valida dati tion on revi review ew must must be be est estab abli lish shed ed to main mainta tain in th the e val valid idat ated ed st stat atus us of the the cleaning procedures.

2.4 .47 7

Fr Fre equen uency for for up upda dati tio on of of cl clean eaning vali alidatio tion ma matri trix, 



 As and when equipment equipment worst case changes or next product changes for acceptance criteria, version of individual equipment chain shall be changed. (if applicable) Respective chain shall be reviewed for inclusion / deletion of equipment’s or entry of new product / transfer of product / discontinuation of product from the site from the site as per   Annexure 1035-G-0038/A4. 1035-G-0038/A4.

2.48 2.48

Unit Unit sha shall ll ha have ve shall cont contro rol l o on n the the fol follo lowi wing ng when for forma mats ts wit with h hel help p of of vers versio ion n num numbe berr on it it.. Belo Below w mentioned data be updated as and required.

2.48.1

Equipmentt Chain (Product / Product group wise) with surface area. Equipmen

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

Note:

Equipment which is similar in design and function may be grouped and a worst case can be established establishe d for validation. validation.

2.49 2.49

Reva Revali lida dati tion on:: Rev Reval alid idat atio ion n sha shall ll be carr carrie ied d out out in th the e fol follo lowi wing ng si situ tuat atio ions ns::

2.49.1

Revalidation in case of changes in equipment / product contact parts / change in source of   API, if required, based on impact assessment, cleaning procedure or cleaning aid (For  example: Cleaning agent) cleaning validation shall be initiated. Revalidation Revalidati on to be carried out if the formulation of an existing cleaning agent is changed.

2.49.2

Periodic revalidation:

2.49.2.1

For non-betalactum antibiotics and non-sexual hormones-c hormones-corticosteroids: orticosteroids: one batch cleaning validation for each worst case product shall be done once in a year.

2.49.2.2

For other products:

2.48.2 2.4 8.2.2. .2.1 1 Perfor Perform m an annua annuall clean cleaning ing revie review w repor reportt in a schedu scheduled led manne mannerr an and d do docum cumen entt as pe per  r  annexure no. 1035-G-0038/A14 1035-G-0038/A14.. Based on the review there could be one one of the conclusion: 1.

2.

3.

The data data revi review ew defin definite itely ly suppo supports rts the the conclu conclusio sion n that that the clea cleanin ning g proces process s is in a state state of  control, and therefore is still validated. With such a conclusion, there is no need for protocol runs on any products within group. The data data revi review ew sugge suggests sts that that the the clean cleaning ing proc process ess may may not not be in a state state of of contro control. l. Pe Perfo rform rm one protocol protocol run on the worst case product. product. If successful, successful, the cleaning cleaning process is considered validated for all products in the group. For example but not limited to: An OOS is observed but there is insufficient evidence to prove that it is due to the previous product. The data data revie review w suppo supports rts the the conclu conclusio sion n that the the cleani cleaning ng proce process ss is defin definite itely ly not not in a state state of control. Conduct an investigation to bring it into a state of control and then perform three protocol runs on the worst case product. For example but not limited to: An OOS is observed but there is sufficient evidence to prove that it is due to contamination from previous product. product.

2.48.2 2.4 8.2.2. .2.2 2 Reval Revalida idatio tion n shall shall be do done ne for one batch batch per worst worst case product product in 5th year after the last successful run. 2.50 2.50

Refe Referr Ann Annex exur ure e 103 10355-GG-00 0038 38/A /A5 5 for for flow flow diag diagra ram m of of cle clean anin ing g val valid idat atio ion. n.

2.51 2.51

Foll Follow owin ing g are are the the doc docum umen ents ts whic which h sha shall ll have have spec specif ific ic docu docume ment nt num numbe bers rs and and sha shall ll be version controlled :   

2.51.1

List of case equipment chains (applicable for equipment chain concept) Worst document Sampling plans Document number for Worst case document shall be; WC/XXXXXXX/01

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

EFFECTIVE DATE

12-Jun-2018

WHERE; WC- WORST CASE XXXXXXX- Equipment name in short with capacity (if applicab applicable) le) 01-serial number  For example : For octagonal blender blender 2250 litres WC/BLD2250/01 2.51.2

Sampling plan for each equipment / equipment chain shall be prepared unit wise and the document number shall be; SP/XXXXXXX/01 SP-sampling plan XXXXXXX- Equipment name in short with capacity (if applicab applicable) le) 01-serial number  For examp example le : For octago octagona nall blend blender er 225 2250 0 litre litres s SP/BLD2250/01 Refer specimen Annexure 1035-G-0038/A10 for sampling plan. The numbering system for above documents shall be decided as per different dosage forms, unit wise. List of document numbers shall be available at the unit as per Annexure 1035-G-0038/A8.

2.5 .52 2

The The w wo ors rstt c cas ase e do docu cume ment nt sh shal alll h hav ave e fol folllowing con conte tent nts: s:     

3.1

Equipment chain (applicable Equipment (applicable for equipmen equipmentt chain concept) Equipmentt details, such as equipment code, capacities and surface area. Equipmen Product list Determination Determina tion of worst case products for both present and next product of each criterion. Summary of worst case products. ABBREVIATIONS : % ° µg  API B. No. BW cGMP

: : : : : : :

Percentage de degree Micro gram Active Pharmaceutical Pharmaceutical Ingredient Ingredient Batch number   body weight of patient taking next product (50 kg) Current Good Manufacturing Practices

cm D HT GC HPLC ICH inch2

:: : : : :

Ciertnytih moeldtretime D Gas Chromatography High Performance Liquid Chromatography International Conference on Harmonisation square inch

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

4.0

EFFECTIVE DATE

12-Jun-2018

Kg LD50 LOD LOEL Lt. mg ml mm MSDS

: : : : : : : : :

Kilogram The 50% let lethal hal dose dose of the the targe targett res residu idue e in an an anima animall Limit of detection Lowest Observed Effect Level Litre Milligram Millilitre millimetre Material Safety and Data Sheet

NOAEL NOEL OOS PDE PLC ppm PVC QC SOP Sq. Sr. no. STV TI

: : : : : : : : : : : : :

No Observed Adverse Effect Level No Observable Effect Level Out of specification. Permitted Daily Exposure Programmable Logic Control Parts per million Polyvinyl Chloride Quality Control Standard Operating Procedure Square Serial Number   Safe threshold value Technical Information typically in mg / kg of body weight (by the appropriate route of administration) administration)

TO CC U PL UV WHO

:: : :

T orig c ig ca Uolttraal M craoniH hrb Poenrformance Liquid Chromatography Ultra Violet World Health Organisation

REFERENCES

:

WHO Technical Report series 937, fortieth report 1035-G-G-0024 : Ri Risk Ma Management By By F Fa ailure Mo Mode, Ef Effe fec ct An And Cr Criti tic cality Analysis 1035-G-G-0209 : To de deter termine an and implement pe permitte ted d da daily ex exposure (P (PDE) va value. CTG 18 : Development of cleaning procedure. 1035-L-0071 : Mi Microbiological mo monitoring of of s su urfaces in in pr production ar area. PDA Technical Report 29 – Points to consider for cleaning validation. EMA’s Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. f acilities. ISPE guide Volume 7 “Risk-based “Risk-based Manufacture of Pharmaceutical Pharmaceutical Products”. ICH Topic Q3C (R4) : Impurities: Guideline for Residual Solven Solvents. ts. MINISTRY OF SOCIAL PROTECTION RESOLUTION NUMBER 3028 OF 2008 (August 13)

 

DOCUMENT NAME

CLEANING VALIDATION AND ESTABLISHMENT OF WORST CASE PRODUCT

DOCUMENT No No.

1035-G-0038

VERSION No.

6.5, CURRENT

DATE OF ISSUE

14-May-2018

5.1

ANNEXURES Annexure Number  1035-G-0038/A1

EFFECTIVE DATE

12-Jun-2018

: Annexure Name

To be used as

1035-G-0038/A3

“Label for cleaning validation samples”(1035-G0038/LA1/1) Cleaning validation matrix and establishment of worst case product (1035-G-0038/F1/2) (1035-G-0038/F1/2) Summary of cleaning validation (For single equipment)

1035-G-0038/A4

(1035-G-0038/F2/1) Review of of w wo orst c ca ase pr product ((1 1035-G-0038/F3/1)

1035-G-0038/A2

1035-G-0038/A5 1035-G-0 1035 -G-0038/A 038/A6 6

Flow diagram of validation and implementation validated cleaning procedure (1035-G-0038/FL1) (1035-G-0038/FL1) Validatio Validation n Protocol Protocol for clea cleaning ning of equipme equipment nt (1035-G-0038/P1/4)

Specimen Copy Specimen Copy Specimen Copy Specimen Co Copy

of   Reference Copy Specimen Copy

10 103535-G-0 G-0038 038/A7 /A7

Val Valid idati ation on Repor Reportt for cleani cleaning ng of equipme equipment nt (1035-G-0038/R1/4)

Specimen Copy

1035-G-0038/A8

List of documents (1035-G-0038/F4/1)

Specimen Copy

10 1035 35-G -G-0 -003 038/ 8/A9 A9

Comm Common on surf surfac ace e area area of equi equipm pmen ents ts (103 (10355-GG-00 0038 38/F /F11 11))

Spec Specim imen en Copy Copy

Cleanin ning val validati datio on samp samplling pl plan(1 an(10 035-G5-G-0 0038/ 8/F6 F6/2 /2))

Speci pecim men Co Copy

103 10 35-G-G-003 0038/A /A1 10

1035-G-0038/A11 New Product Introduction Cleaning Review Report (1035-G-0038/F7/1) 1035-G-0038/A12 Cleaning validation summary of new product (1035-G-0038/F8/2) Prerequisite te checklist for cleaning validation 1035-G-0038/A13 Prerequisi (1035-G-0038/CL1/3) 1035-G-0038/A14  Annual cleaning cleaning review report report (1035-G-0038/F9/2)

Specimen Copy Specimen Copy Specimen Copy Specimen Copy

 

ANNEXURE 1035-G-0038/A1 (SPECIMEN COPY)

Location

LABEL FOR CLEANING VALIDATION SAMPLES

Locaton

VALIDATION SAMPLE : RINSE / SWAB PRODUCT: B.NO.: EQUIPMENT / PART NAME : SAMPLE / VOLUME : STATUS: ACTIVE / CLEANING AGENT NAME OF ACTIVE : SAMPLE NO.: SIGNATURE:DATE: SIGNATURE:DA TE: SAMPLING TIME: ANALYSIS DUE DATE/ TIME: (1035-G-0038/LA1/1)

Page 1 of 1

 

ANNEXURE 1035-G-0038/A2 (SPECIMEN COPY)

Location No.: WC/XXXXXXX/01

Version No.:

CLEANING VALIDATION MATRIX AND ESTABLISHMENT OF WORST CASE PRODUCT 

Supersedes: --- 

Equipment / Equipment chain no.: PRODUCT

Active

Department :

Solubility  Streng  Potenc 

Ingredien in Washing  t h t 

solvent 

Effective Date:

*LD 5 50 0

y (mg)

(mg)

NOEL/

PDE 

Suitable

Batch

NOAE 

Value

Swabbin

size

L  / LOEL

(permitted  daily 

g Solvent 

Kg (S)/  Batch

exposure)

Maximu  Referenc  m Daily  e Chain dose (J) No.

Commo

K/J

n

Ratio

Surface  Area (inch2  )

size Nos. (K)

(1035-G-0038/F1/2)

Page 1 of 2

 

Location     

Very Soluble : VS   Freely Soluble : FS   NOEL : No observed effect level.

   

Soluble Sparingly Soluble

: :

S   SPL

Slightly Soluble Very Slightly Soluble Practically In Insoluble

   

 

: : :

SLS   VSLS   INS  

LD 50 : If NOEL not available then only LD 50 value should be considered. Conclusion : Worst Products to be validated  Product having least solubility

:

Product having least Therapeutic dose (potent drug) Product having least PDE value (Toxic drug)

:

Worst Product for Calculation of Acceptance Criteria Product having Minimum batch size and Maximum Daily Dose (Based on Minimum K/J Ratio)

Prepared By  Quality   Assurance

 Approved By  Head Unit Quality Assurance

Noted By  Unit Head  

 

ANNEXURE 1035-G-0038/A3 (SPECIMEN COPY)

Location

SUMMARY OF CLEANING VALIDATION (FOR SINGLE EQUIPMENT) PRODUCT:

EQUIPMENT:

CONTENT:

EQUIPMENT CODE NO. :

CLEANING SOP NO.: LIMIT OF DETECTION (FOR RINSE   )  ):: LIMIT OF DETECTION (FOR SWAB): LIMIT OF DETECTION CLEANING AGENT (FOR RINSE/SWAB if applicable):

PART  OF  SR. NO.

THE  EQUI  -  MEN  T 

CONTENT  OF ACTIVE  INGREDIEN 

CONTENT  OF  DETERGEN 

CONTENT  OF   ACTIVE 

CONTEN  T OF  SOLVENT  IN FINAL RINSE 

T IN FINAL RINSE (mg/4 or 16 sq. inch)

T IN FINAL RINSE (mg/4 or 16 sq. inch)

INGREDI-  ENT IN  SWAB (mg/4 or  16 sq. inch.)

(IF   APPLICA - BLE) (mg/4 or  16 sq. inch)

BIOBURDEN 

VISUA L INSPE-  CTION 

TOTAL COUN  T  (Cfu/  swab  )

FUNGA L COUNT  (Cfu/  swab  )

Visually  Clean

Limit Batch No.:

Name of operator:

Chemical A.R. No.

Micro A.R. No.

Batch No.:

Name of operator:

Chemical A.R. No.

Micro A.R. No.

Batch No.:

Name of operator:

Chemical A.R. No.

Micro A.R. No.

(1035-G-0038/F2/1)

Page 1 of 2

 

Location

SUMMARY OF CLEANING VALIDATION (FOR SINGLE EQUIPMENT) DEVIATION, IF ANY

:

OUT OU T OF OF SPE SPECI CIFI FICA CATI TION ON,, IF ANY ANY

:

CONCLUSION

:

From the data of validation, it is concluded that cleaning of as per SOP No.: removes previous product residues, cleaning agent and microbial contaminant up to  predetermined  predetermine d acceptance level and there is no risk of cross contamination in subsequent   product . RECOMMENDATIONS

:

From above data it is concluded that SOP for cleaning procedure of equipment    stands validated. It is recommended recommended to follow standard cleaning procedure for equipment equipment REVALIDATION

. :

PREPARED BY:

APPROVED BY:

QUALITY ASSURANCE Date:

HEAD UNIT QUALITY ASSURANCE   Date:

NOTED BY:

UNIT HEAD Date:

 

ANNEXURE 1035-G-0038/A4 1035-G-0038/A4 (SPECIMEN COPY)

Location

REVIEW OF WORST CASE PRODUCT  Equipment/ Equipment chain no.: Date Product   Active Ingredient  Ingredient  Batch Size In Kg/Nos. Strength (mg / unit dose) Solubility in washing solvent  Suitable Swabbing solvent  Least therapeutic  potency (mg) LD50  NOEL/ NOAEL/ LOEL PDE Value (Permitted Exposure) Daily Maximum Daily Dose (Nos.) K/J Ratio Remark  Done by/Date Reviewed by/Date NOTE : 1. If NOEL is not available available then go for LOEL. 2. If NOEL/NOAEL/LOEL value is not available then NOEL should be calculated based LD NOEL: No observed effect level. Page 1 of 1

50.

(1035-G-0038/F3/1)

 

ANNEXURE 1035-G-0038/A5 1035-G-0038/A5

Corporate Location:

FLOW DIAGRAM OF VALIDATION AND IMPLEMENTATION OF VALIDATED CLEANING PROCEDURE  Define the programme and validate the method Identify the scope of the exercise Develop a cleaning procedure based on cGMP and past  experience Write and execute validation protocol / report for  cleaning  Collect data for each product  Perform cleaning validation for each product till the worst case product identification Identify worst case product  Calculate the acceptance criteria Perform cleaning validation exercise

Introduction of new product in facility  Risk assessment for cleaning validation of new product  Worst case product 

Yes Perform cleaning validation exercise with 3 batches

No Perform cleaning validation exercise with 1 batch Monitoring of cleaning  procedure for  physical characteristics and record the results in  Annexure 1035-G0038 /A12 

Review of risk assessment based on test result of first batch and review of Annexure 1035-G0038 /A12 

Page 1 of 1

(1035 G 0038/FL1)

 

ANNEXURE 1035-G-0038/A6 1035-G-0038/A6 Decision for two more batches of cleaning validation

Page 1 of 1

(1035 G 0038/FL1)

 

ANNEXURE 1035-G-0038/A6 (SPECIMEN COPY)

Location

VALIDATION PROTOCOL Date of Issue :

Protocol No.: CVP 01 Version No. :

CLEANING OF EQUIPMENT

Supersedes : 1.0

Effective Date : Page 1 of 12

Objective

:

To validate the effectiveness of the cleaning procedure for removal of product residues of the previous product, cleaning agents, solutions/solvents microbial residue, odour and colour up to a predetermined acceptance level and to ensure that there is no risk associated with contamination contaminatio n into subsequent product. 2.0

Scope

:

 Applicable to cleaning procedures of equipment equipment and accessories accessories used in manufacturing manufacturing of  pharmaceutical pharmaceutic al products. 3. 3.0 0

Just Justif ific icat ation ion for for sel selec ecti tion on of ite item/ m/ equ equip ipme ment nt /ac /acce cess ssor ory y /pro /proce cess ss /pr /prod oduc uctt / sys syste tem. m. Justification for selection shall be recorded in the report.

4.0

Site of the Study : The site of study shall be entered in the validation report.

5. 5.0 0

Desc Descri ript ptio ion n of Equ Equipm ipmen entt / ac acce cess ssor ory y whic which h is c cle lean aned ed a and nd det detai ails ls of of the the Nex Nextt prod produc uct: t: Details of Equipment Equipment / accessory accessory name and code no. no. used for (product name), Batch Number, active ingredients, date of validation and details of next product shall be recorded in the report.

6.0

Responsibility an and Tr Training: Trained personnel shall perform cleaning validation. validation. Details of training shall be recorded in the report for : Production, Production, Quality Assurance, Quality Control, Engineering Engineerin g and others (Individual names shall be entered in the report).

7. 7.1 1

Stan Standa dard rd Oper Operat atin ing g Proc Proced edur ures es (S (SOP OPs) s) to be fo foll llow owed ed::

7.2

Standa Standard rd Operat Operating ing Proced Procedure ure for cleani cleaning ng of equi equipme pment. nt. SOP No. No. a alon long g with with versio version n numb number  er  shall be recorded in the report.

7.3

Standa Standard rd Operat Operatin ing g Proc Procedu edure re for sampli sampling ng of rrin inses ses an and d swa swabs. bs. SOP No. along along with with versi version on number shall be recorded in the report.

7.4

Standa Standard rd Operat Operating ing Pro Proced cedure ure for cleani cleaning ng val valida idatio tion n and and establ establish ishmen mentt of of wors worstt case case product. SOP No. along with version number shall be recorded in the report.

(1035-G-0038/P1/4)

 

Location

VALIDATION PROTOCOL Date of Issue :

Protocol No.: CVP 01 Version No. :

CLEANING OF EQUIPMENT

Supersedes :

Effective Date : Page 2 of 12

7.5 7.5

Mi Micr crob obio iolo logi gica call meth method od alon along g wi with th vers versio ion n nu numb mber er fo forr Bio Biobu burd rden en st stud udie ies s of of equi equipm pmen entt shal shalll be recorded in the report.

7. 7.6 6

Appr Approv oved ed sa samp mpli ling ng plan plan no. no. s sha hall ll be re reco cord rded ed in th the e rep repor ort. t.

8.1

Controls :

8.2

Requirements:

8.2.1 8.2 .1

Measu Measurem rement ent of of the foll follow owing ing shal shalll be done done using using vali valida dated ted anal analyti ytica call methods methods:: a) active ingredient ingredient of previous product product in swabs a and nd rinses. b) removal of cleaning cleaning agent agent in the final final rinse c) removal of solvent solvent / solution solution used for cleaning

8.2. 8.2.2 2

Swab Swab use used d and and its its Lot Lot.. No. No. to b be e rrec ecor orde ded d in the the repo report rt..

Note:

Reference analytical method validation protocol number for the above shall be recorded in the validation report.

8. 8.1. 1.2 2

Vi Visu sual al in insp spec ecti tion on of clea cleane ned dp par arts ts..

8.1.3

Non contact contact parts like seals, seals, fl flang anges, es, heati heating ng eleme elements, nts, ductings ductings of Fluid Fluid Bed Drier, Drier, Fluid Fluid Bed Processor, Processor, Ganscoate Ganscoaterr and outer surface of equipmen equipmentt shall shall be cleaned to ensure ensure absence of traces of previous product.

8.1.4 8.1 .4

Time Time ffram rames es for for stor storag age e of unc unclea lean n equi equipme pment nt sha shall ll be esta establ blish ished. ed.

8.1.5 8.1 .5

Date Date and and time time of of comple completio tion n of manuf manufac actur turin ing g shall shall be be reco recorde rded d in tthe he rep report ort..

8.1. 8.1.6 6

Date Date and and time time of comm commen ence ceme ment nt of clean cleanin ing g shall shall be reco record rded ed in the the repor report. t. Na Name me of the person who has cleaned the equipment shall be written in the validation report.

8.1.7 8.1 .7

Concen Concentra tratio tion n of the cleani cleaning ng agent, agent, water water quali quality, ty, and and volume volume of rinse rinse solut solutio ion n require required d sha shall ll be recorded in the report. As per the approved sampling plan; collect the rinses / swabs from the equipment and its parts separately. The temperature of water shall be recorded in the report, in case hot water is used.

8.1.8 8.1 .8

Time Time frames frames for stor storage age o off clean clean equi equipme pment nt based based on biob bioburd urden en stu studie dies s shall shall be recor recorded ded in in the report.

8.1.9 8.1 .9

The numb number er of clea cleanin ning g cycles cycles to be perf perform ormed ed shal shalll be record recorded ed in tthe he repo report rt (for (for clean clean in place equipment).

 

Location

VALIDATION PROTOCOL Date of Issue :

Protocol No.: CVP 01 Version No. :

CLEANING OF EQUIPMENT

Supersedes : 8.3

Effective Date : Page 3 of 12

Calibration : Calibrated equipment / instruments shall be used and calibration details shall be recorded in the report.

8.4

Precautions : Ensure that the Main Switch of the equipment is ‘OFF’ before commencement of cleaning.

9.1

Validation Procedure:

Note :

Swab and Rinse sampling shall be done for cleaning validation. However, swab sampling shall be considered as the primary criteria for cleaning validation. If the results of rinse sampling considering the final rinse volume and the Limit of Detection for rinse samples are observed to be more than the acceptance criteria, then only swab sampling shall be done and the cleaning validation exercise shall be concluded based on results of the swab sampling. Rinse sampling shall primarily be used in cases where the surfaces are difficult to reach.

9. 9.2 2

Clea Cl ean n tthe he equi equipm pmen entt a as s per per Stan Standa dard rd Ope Opera rati ting ng Proc Proced edur ure. e.

9.3

Fill Fill checkl checklist ist 10 103535-G-0 G-0038 038/A1 /A13 3 “Prere “Prerequi quisit site e checkl checklist ist for cleani cleaning ng execution of each cleaning validation activity.

9.4 9.4

As pe perr tthe he ap appr prov oved ed samp sampli ling ng pla plan, n, coll collec ectt the the rin rinse ses s / swab swabs s fro from m th the e equ equip ipme ment nt and and its its parts separately.

9. 9.5 5

With Withdr draw aw abou aboutt 100 100 ml aliqu aliquot ots s per per act activ ive e ingre ingredi dien entt from from fina finall rinse rinse / sampl sampled ed rins rinses es for  for  estimation of active ingredient along with about 100ml of blank of final rinse (potable water / purified water / water for injection) as control sample. Send this 100 ml blank of final rinse (potable water / purified water / water for injection) injection) along with rinse samples.

9.6 9.6

Coll Collec ectt abou aboutt 50 ml samp sample le fro from m fina finall rins rinse e for for esti estima mati tion on of cle clean anin ing g agen agent. t.

Note:

The rinse sample shall represent the entire rinse volume.

9.7 9.7

Coll Collec ectt abo about ut 50 ml of samp sample le fr from om fina finall rin rinse se fo forr est estim imat atio ion n of of sol solve vent nt / solu soluti tion on (if  (if  applicable).

9.8

Swab Swab ind indivi ividua duall lly y vari various ous parts parts of the eq equip uipmen mentt per per active active ingre ingredie dient nt for chemic chemical al an and d microbial analysis, analysis, after cleaning the parts, as detailed in the sampling plan.

9. 9.9 9

Micr Microb obia iall sw swab abs s shal shalll be take taken n prio priorr to che chemi mica call swab swab sam sampl plin ing. g.

valida validatio tion” n”

before before

 

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CLEANING OF EQUIPMENT

Supersedes :

Effective Date : Page 4 of 12

9.10 9.1 0

Estima Estimate te the the conte content nt of of active active ingr ingred edie ient nt in rin rinses ses / swabs swabs as per per the the vali validat dated ed equa equali lity ty Control method.

9. 9.11 11

Anal Analys yse e th the e swab swabs s fo for mic micro robi bial al grow growth th..

9.12 9.1 2

Confir Confirm m the the remov removal al of of clean cleaning ing agen agentt and and solu solutio tion/s n/sol olven ventt used used in the fin final al rins rinses. es.

9.13 9.1 3

Visua Visually lly in inspe spect ct the fin final al rinse rinse of eac each h part part of equip equipmen mentt tto o ensu ensure re that that iitt iis s clear clear an and d colorless.

9.14 9.1 4

Visua Visually lly insp inspect ect the the equip equipmen mentt surfac surface e to ens ensure ure tha thatt it is cle clean an and and ensu ensure re that that it is free free from from the characteristic odour of flavours if used in the previous product.

9.15 9.1 5

Based Based on the the resul results ts of anal analysi ysis, s, calcu calculat late e the amou amount nt of acti active ve ingr ingred edien ientt and clea cleani ning ng agent agent present in each rinse / swab, microbial microbial growth in the swab and estimate probable contamination contaminatio n in the next considered product.

9.16 9.16

Calc Calcul ulat ate e the the lim limit its s for for acce accept ptan ance ce cr crit iter eria ia as foll follow ows: s:

9.16.1 9.1 6.1

Limits Limits of ac accep ceptan tance ce criter criteria ia for swab: swab:

9.16.1 9.1 6.1.1 .1 Dose Dose cr crite iterio rion n FORMULA:  I x K J L where,

x M = mg of previous product / 4inch2 or 16 inch2

I J

= 0.001 of minimum therapeutic dose of pr previous product in mg. = Maximum number of dosage units of next considered product taken/day. = Surface area of equipments common for both the products (p (pre revi viou ous s prod produc uctt and c con onsi side dere red d next next produ product ct)) = Number of do dosage units per batch of next considered product. = 4 or 16 (for reporting results per 4 inch2 or 16 inch2)

L K M

9. 9.16 16.1 .1.2 .2 10 ppm ppm cri crite teri rion on FORMULA: Rx S x U T

=

mg of pre revi viou ous s prod produc uctt / 4 inch inch2 or 16 inch2

 

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Effective Date :

CLEANING OF EQUIPMENT

Page 5 of 12

= 10 mg active tive ing ingredi redie ent in previ revio ous pro product / kg of nex extt co con nsi sid dered red prod roduct ct.. = Mi Minimum Batch size in kilograms / lliitr tre es of ne next c co onsidered product. = Surface ar area of of eq equipments co common fo for bo both th the e pr products (previous pr product and considered next product) = 4 or 16 (for reporting results per 4 inch2 or 16 inch2)

PDE cr criterion: Formula to get safe threshold value (STV) : PDE X K X M = J L

mg of previous product / 4 inch2 or 16 inch2

Where, PDE J L K M 

= Permitted daily exposure = Ma Maximum number of of d do osage units of ne next considered product tta aken / day. = Surface area of equipments common for both the products (previous and considered next product) = Nu Number of dosage units per batch of next considered product = 4 or 16 (for reporting results per 4 inch2 or 16 inch2)

The Permitted Daily Exposure (PDE) is determined by following following equation:

PDE =

NOAEL X weight adjustment F1 X F2 X F3 X F4 X F5

The modifying factors are as follows: F1 =

A facto factorr to account account for extra extrapola polation tion between between species species

F1 =

5 for for extrap extrapol olati ation on from from rrats ats to humans humans

F1 =

12 for extrap extrapola olatio tion n from from mice mice to to huma humans ns

F1 =

2 for for extrap extrapol olati ation on from from d dogs ogs to hu human mans s

F1 =

2.5 for extrap extrapol olati ation on fro from m rabb rabbits its to huma humans ns

F1 = F1 =

3 for for extrap extrapola olatio tion n from from monkey monkeys s to to hum humans ans 10 for for extra extrapol polati ation on fr from om othe otherr anima animals ls to hu human mans s

F2 =

A factor factor of 10 to a accou ccount nt for for variab variabili ility ty betwee between n indivi individual duals s

 

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CLEANING OF EQUIPMENT

Supersedes : F3 = F3 = F3 F3 F3 F3 F4

= = = = =

F4 = F4 = F4 = F4 = F5 =

Note:



Page 6 of 12 A variab variable le factor factor to account account for for toxi toxicity city studies studies of of short-ter short-term m exposur exposure e 1 for studi studies es that that last at at least least one half half lifetim lifetime e (1 year year for rodents rodents or rrabb abbits; its; 7 years years for  for  cats, dogs and monkeys). 1 for reprod reproducti uctive ve studies studies in which which the the whole whole period period o off organogen organogenesis esis is is covered. covered. 2 for a 6-mon 6-month th study study in in rodent rodents, s, or a 3. 3.5-ye 5-year ar study study in non-r non-roden odents. ts. 5 for for a 3-mon 3-month th study study in in rodents rodents,, or a 2-year 2-year study study in non-rode non-rodents. nts. 10 for studi studies es of a sho shorte rterr d dura uratio tion n A factor factor that that may may be applied applied in ca cases ses of of sever severe e toxicit toxicity, y, e.g., e.g., non-ge non-genoto notoxic xic carcinogenicity, carcinogen icity, neurotoxicity or teratogenic t eratogenicity. ity. In studies of reproductive toxicity, the t he following factors are used: 1 for for fetal toxicity toxicity associat associated ed with maternal maternal toxicity toxicity 5 for for fetal fetal toxic toxicity ity witho without ut mate materna rnall to toxic xicity ity 5 for for a terat teratog ogeni enic c effec effectt with with mater materna nall toxi toxicit city y 10 for a teratoge teratogenic nic effec effectt witho without ut mate maternal rnal toxicity toxicity A variable variable factor factor that may be applied applied if the no-effect no-effect level level was not establis established hed.. When only an LOEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.

1.

If values values of individu individual al factors factors are are no nott availabl available, e, then consider consider high highest est value. value.

2.

If the NOEL value value is avai availabl lable, e, F5 facto factorr shall shall be be consid considered ered as 1. 1.

3.

If body body weight weight is consi considere dered d while while calcul calculation ation of NOEL, NOEL, then weigh weightt adjustmen adjustmentt factor shall be considered as 1 while calculation of PDE.

For this approach NOEL shall be estimated from the LD 50 value using the following equation: LD50 X BW

NOEL =

MF1

Effective Date :

MF1

NOEL

=

No Observable Effect Level

LD50

=

th the e 50% 50% leth lethal al dose dose of tthe he targ target et resi residu due e in in an an ani anima mal, l, ty typi pica call lly y iin n mg mg / body weight (by the appropria appropriate te route of administration) administration)

BW

=

body weight of pati tie ent tak taking next product (50 kg) The modifying factor selected shall be not more than 1000.

=

For example, If Alprazolam Alprazolam molecule is considered, considered, Toxicity Oral, mouse: LD50=1020 mg/kg.

NOEL = 1020 x 50 1000

PDE = 51

=

51

= 0.004

12 x 10 x 10 x 10

kg of 

 

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CLEANING OF EQUIPMENT

Supersedes :

Effective Date : Page 7 of 12

STV (safe threshold value) : 0.004 X K X M = L 9.16.2 9.1 6.2

Jmg of previous product / 4 inch2 or 16 inch2

Limits Limits of ac accep ceptan tance ce cr crite iteria ria for rinse: rinse: The most stringent stringent limits limits of acceptance acceptance criterion of swab that that would emerge emerge from dose criterion, 10 ppm criterion and PDE criterion, that acceptance criterion shall be used to derive the limits for the acceptance criterion of rinse. Derive the acceptance criterion for rinse by using following formula:

9.16.2.1 9.16 .2.1 Dose criterio criterion: n: Formula:  I J

X K X A = L B

ppm of prev previous ious prod product uct

Where, I J L K  A B

= 0. 0.001 of minimum therapeutic dose of previous product in mg. = Ma Maximum number of of d do osage units of ne next considered product tta aken / day. = Surface ar area o off e eq quipment’s co common fo for bo both th the pr products (p (previous an and considered next product) = Nu Number of dosage units per batch of next considered product = Area of specific equipment equipment sampled = Quantity of final rinse/ sample rinse in kg or Litre

9.16.2.2 9.16 .2.2 10 ppm Criterion Criterion : Formula: RX S X A= T B Where,

ppm of prev previous ious product produ ct

R S

= 10 10 mg acti ctive ingredi redie ent in previ revio ous pr pro oduct / kg of ne next co con nsi sid dered red produ roduct ct.. = Minimum Batch tch size in kilograms / litr tre es of ne next considered product.

T

= Surface ar area of of equipment’s com common for for both th the pr products (pr (previous and and considered next product) = Area of specific equipment equipment sampled = Quantity of final rinse/ sample rinse in kg or Litre

 A B

 

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CLEANING OF EQUIPMENT

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9.16.2 9.1 6.2.3 .3 PDE criteri criterion: on: Formula to get safe threshold value (STV) : PDE X K X A = L B

Jppm previous product

Where, PDE

= Permitted daily exposure

J L

= Ma Maximum number of of d do osage units of ne next considered product tta aken / day. = Surface ar area o off e eq quipment’s co common fo for bo both th the pr products (p (previous an and considered next product) = Nu Number of dosage units per batch of next considered product = Area of specific equipment equipment sampled = Quantity of final rinse/ sample rinse in kg or Litre

K  A B

9.17 9.1 7

Compar Compare e the the amoun amountt of resid residue ue of of the p prev revio ious us prod product uct a agai gainst nst resp respect ective ive establ establish ished ed acceptance criteria for rinse and swab.

Note :1. :1. In case of low acceptance criteria more area can be considered for swabbing for example – 16 sq inch. 2. If NOEL is not not available available then then go for LOEL. LOEL. 3. If NOEL/NOAEL/LOEL value value is not available then NOEL sh shall all be calculated based based LD50. 4. For sin single gle drug drug,, LD50 value may be available for more than 1 species, but sensitivity may vary from species to species. Sensitivity is shown in decreasing order as Monkey-----------Dog------Monkey-----------Dog-----------Rat--------------Mice. LD50 value of Rat / Mice shall be considered for calculation. 5. LD50  value differ based on the type of formulations/Route of administration. While doing calculations for cleaning validation LD 50 value to be selected based on formulations/Route of  administration. If LD 50 value is not available for other route of administration/ formulation then oral route LD 50 shall be considered. 6. If LD LD50 varies with respect to API supplier then lowest LD 50 value of same species between two suppliers shall be considered. 7. For weight weight adjustmen adjustmentt consider consider 50 kg for human medicina medicinall product product and 1 kg for veterinar veterinary y products. 10

Acceptance criteria:

10 10.1 .1

The most most stri string ngent ent limi limitt of accept acceptanc ance e that that wou would ld emer emerge ge from from Dose Dose crit criteri erion on 10ppm 10ppm crit criteri erion on and PDE criterion shall be applied during validation exercise along with visual verification.

 

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CLEANING OF EQUIPMENT

Supersedes : 10 10.2 .2

Effective Date : Page 9 of 12

Clean Cleanin ing g agents agents used used sha shall ll be easi easily ly remov removabl able. e. The The accep acceptan tance ce crite criteria ria for for clea cleanin ning g agent agent shall be calculated calculated by determining determining the carryover carryover to next product through Safe Safe Threshold Value derived derived from PDE criteria criteria similar similar to that used used for API, for every every equipment. The cleaning agent shall not be more than this calculated acceptance criteria.

Note: Acceptance Note:  Acceptance criteria criteria for cleaning agent agent can be calculated by usi using ng PDE value. STV (Acceptance (Acceptance criteria) can be derived by using below mentioned formula Formula to get safe threshold value (STV) for Rinse: PDE PD EX K X A = L B Where, PDE J L K  A B Note :

Jppm of cleaning agent

= Pe Permitted daily exposure = Max Maxiimum mum numbe mber of dos dosag age e units nits of ne next co con nsi sid dered red produ roduc ct ta take ken n / day ay.. = Surf Surfa ace area rea of equ equiipmen ment’s t’s com commo mon n fo for bot both h th the e pr pro oduct cts s (p (previ revio ous and and considered next product) = Nu Number of do dosage units per batch of n ne ext considered product = Area of specific equipment equipment sampled = Quantity of final rinse/ sample rinse in kg or Litre

For Veterinary and Topical products where safe threshold value (STV) cannot be calculated,

in such cases 10 ppm criteria shall be used. 10 10.3 .3

The eq equip uipmen mentt and and its its parts parts sh shall all be fre free e fr from om odo odour ur when when fla flavou vours rs are are used used in the formulation.

10 10.4 .4

The fina finall rinse/ rinse/ samp sample le rinse rinse sha shall ll be be visua visuall lly y clear clear and and colour colourle less ss when when colo colours urs are are used used in in the formulation. formulation.

10 10.5 .5

Biobur Bioburde den n on equ equipm ipment ent shal shalll compl comply y the li limit mits s of Micr Microbi obiol ologi ogical cal spe specif cific icati ation. on.

10 10.6 .6

There There shal shalll not not be any any trac traces es of of solven solventt / soluti solution on in in the the fina finall ri rinse nse,, if solve solvent nt / solu solutio tion n used used for cleaning.

10 10.7 .7

Clean Cleaning ing proc proced edure ure tha thatt consi consiste stentl ntly y en ensur sures es all all the abov above e can be rega regarde rded d as va valid lidate ated. d.

Note: Swab recovery factor shall be considered for calculation during validation, apply recovery factor (obtained (obtained from validation validation study) for calculating the content if the same is found found less than 100 %. If recovery is observed more than 100 %, do not apply factor for calculation. calculation.

 

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CLEANING OF EQUIPMENT

Supersedes :

11

Effective Date : Page 10 of 12

Details of Deviation / OOS: Details of deviations (including justification of acceptance, if any) to successfully carry out the validation exercise and any OOS results obtained shall be reported. (Attach the details in the Validation report).

12

Type of Validation: Concurrent validation validation / Revalidation Revalidation (Type of validation validation to be recorded in the validation report)

13

Frequency:

13 13.1 .1

Concur Concurren rentt valida validatio tion: n: Three Three conse consecut cutive ive succ success essful ful valid validati ation on studi studies es per per equip equipmen mentt based based on the worst case.

13.2 13.2

New New Prod Produc uctt as per per wors worstt ca case se / new new equi equipm pmen entt / Chan Change ge in cle clean anin ing g proc proced edur ure: e: Th Thre ree e successful validation studies per equipment.

13 13.3 .3

In case case any any new new prod product uct is intr introdu oduced ced in faci facili lity, ty, Ris Risk k asses assessme sment nt to be perf perfor ormed med for  evaluati eval uation on of worst worst case product product for cleanin cleaning g validati validation. on. if the product product is identified identified to be a worst case three successful validation studies, If the product is not identified as worst case, then full cleaning validation will be performed for the first batch.

13 13.4 .4

Revali Revalida datio tion: n: Reva Revalid lidati ation on sha shall ll be be carri carried ed out out in in th the e foll followi owing ng situ situati ation ons: s:

13.5

Periodic rre evalidation:

13.5.1 13.5 .1 For non-betal non-betalactum actum antibiot antibiotics ics and non-sexual non-sexual hormoneshormones-cort corticos icosteroi teroids: ds: one batch cleaning cleaning validation for each worst case product shall be done once in a year. 13 13.5. .5.2 2 For othe otherr produc products: ts: 13.5.2.1 Perform an annual annual cleaning cleaning review report report and document document as per annexure annexure no. 1035-G0038/A14. Based on the review there could be one of the t he conclusion: conclusion: 1. The data review review definit definitely ely supports supports the conclus conclusion ion that the cleanin cleaning g process process is in a state of  control, and therefore is still validated. With such a conclusion, there is no need for protocol runs on any products within group. 2. The data data review review suggest suggests s that the cleanin cleaning g proce process ss may not be in a state of control control.. Perform one protocol run on the worst case product. If successful, the cleaning process is considered forinsufficient all products in the group. Forthat example but to:product. An OOS is observed validated but there is evidence to prove it is due to not the limited previous 3. The data data review supports the the conclusion conclusion that that the cleaning cleaning process is is definitely definitely not in a state of control. Conduct an investigation to bring it into a state of control and then perform

 

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CLEANING OF EQUIPMENT

Supersedes :

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three protocol runs on the worst case product. For example but not limited to: An OOS is observed but there is sufficient evidence to prove that it is due to contamination from previous product. 13 13.5. .5.2.2 2.2 Revali Revalidat dation ion shall shall be done for one batch batch pe perr worst worst case produ product ct in 5 th year after the last successful run. 13 13.6 .6

Reva Revali lida dati tion on in in case case of chan change ges s in equi equipm pmen entt / produc productt conta contact ct part parts s / chang change e in sour source ce of  of   API, if required, based on impact assessment, cleaning procedure or cleaning aid (For  example: Cleaning agent) cleaning validation shall be initiated.

Note:

Revalidation Revalida tion to be carried out if the formulation of an existing cleaning agent is changed.

14

Risk Management Study : The Details of the Risk Management Study to be recorded in the Validation Report.

15

Results / Observations: Record the observations during the study and results obtained from Quality Control Department in the Validation Report.

16

Summary of the validation activity: Summarize the findings of the validation study to draw an inference.

17

Reco Re comm mmen enda dati ons scleaning (In (Incl clud udin ing g req requir uirem emen ents ts of an any y a add ddit itio iona nall do docu cume ment ntat atio ion n / cha chang nges es to be made in tion the SOP): Record the recommen Record recommendati dations ons based based on the interpre interpretatio tation n of the results results of the Validatio Validation n Report.

18

Team approval: The personnel who have performed the validation study, supervised the validation, validation, completed the records, monitored the maintenance of equipments, performed the testing of the product shall approve the validation validation report.

19

Review (i (inclu lus sive of of ffo ollo llow up up a ac ction, if if an any): The Validation Report shall be reviewed by Head Unit Quality Assurance. The report shall include any follow up action if required.

20

Approved and Noted by : Validation Report shall be finally approved by Head Unit Quality Assurance and noted by Unit Head

 

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CLEANING OF EQUIPMENT

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21

Page 12 of 12

Attachments :    

22

Effective Date :

Technical information sheet of cleaning validation sample analysis.  Approved sampling sampling plan with with swab location. location. Common surface area of equipment Prerequisite checklist for cleaning validation ABBREVIATIONS

:

No.  A.R.No. ml QC mg inch2 ppm µg % OOS MSDS PDE NOEL NOAEL LD50

: : : : : : : : : : : : : : :

BW LOEL STV

: : :

Number   Analytical Reference Reference number  number  Millilitre Quality Control Milligram square inch Parts Per Million Microgram Percentage Out of specification Material Safety and Data Sheet Permitted Daily Exposure No Observable Effect Level No Observed Adverse Effect Level the 50% lethal dose of the target residue in an animal, typically in mg / kg of body weight (by the appropriate route of administration) administration) body weight of patient taking next product (50 kg) Lowest Observed Effect Level Safe threshold value

 

ANNEXURE 1035-G-0038/A7 (SPECIMEN COPY)

Location [

VALIDATION REPORT Date of Issue :

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CLEANING OF EQUIPMENT

Supersedes :

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Batch Number:

REFERENCE PROTOCOL PROTOCOL NO. : CVP 01, Version -

Product Name: 1.0

Objective : To validate the effectiveness of the cleaning procedure for removal of product residues of the previous product, cleaning agents, solutions/solvents solutions/solvents microbial residue, odour and colour upto a predetermined acceptance level and to ensure that there is no risk associated with contamination contaminatio n into subsequent product.

2.0

Scope :  Applicable to cleaning procedures of equipment equipment and accessories accessories used in manufacturing manufacturing of  pharmaceutical pharmaceutic al products.

3.0

Justif Justifica icatio tion n for sele selecti ction on of item item / equi equipm pment ent / acce accesso ssory ry / proce process ss / produ product ct / syste system. m.

4.0

Site Of The Study

5. 5.0 0

Desc Descri ript ption ion Of Equ Equip ipme ment nt / Acce Access ssor ory y Whic Which h Is Cl Clea eane ned d: Carry out validation as per Validation Protocol No. CVP 01, Version

:

Equipmentt : Equipmen Date of validation: Previous product: Code Number / Equipmentt chain no.: Equipmen  Active ingredients: ingredients: Next considered worst product based on least batch size and maximum daily dose from the list of the products manufactured using the equipment for which validation to be done Next considered worst product: Batch Size:

Maximum daily dose:

(1035-G-0038/R1/4)

 

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VALIDATION REPORT Date of Issue :

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CLEANING OF EQUIPMENT

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Batch Number:

REFERENCE PROTOCOL PROTOCOL NO. : CVP 01, Version -

6.0

Respo Responsi nsibil bility ity And And Trai Trainin ning: g: (Indiv (Individu idual al Names Names Shall Shall Be Entere Entered) d)

Department

Name

Training Status

Training reports availability

Trained For activity (for  example, Testing / Operation / Sampling)

Ckd. by

Production Quality  Assurance Quality Control Engineering

Others

7. 7.1 1

STAN STANDA DARD RD OPER OPERAT ATIN ING G PROC PROCED EDUR URE E (SOP (SOP)) TO BE FOLL FOLLOW OWED ED :

7.2 7.2

SOP SOP fo forr cl clea eani ning ng of equi equipm pmen ent: t: SOP SOP No.: No.:

, Ve Vers rsio ion n No.: No.:

.

7.3

SOP fo forr sampli sampling ng of rinses rinses an and d swabs: swabs: SOP No.: No.:

, Versi Version on No.: No.:

.

7.4

SOP for for cleani cleaning ng valid validati ation on and and establ establish ishmen mentt of worst worst case prod produc uctt and sampl sampling ing of of rinses rinses and swabs: SOP No.: , Version No.: .

7.5

Microb Microbiol iolog ogica icall metho method d for Biobu Bioburde rden n studie studies s of eq equip uipmen ment: t: No.: No.:   .

7.6

App Approve roved d sampl ampliing plan No.:

, Versio Version n No. No.

.

 

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VALIDATION REPORT Date of Issue :

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CLEANING OF EQUIPMENT

Supersedes :

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Batch Number:

REFERENCE PROTOCOL PROTOCOL NO. : CVP 01, Version -

8.1

Controls:

8.2

Requirements:

8.2.1 8.2. 1

Measurem Measurement ent of the follow following ing shall shall be done done using using validated validated analyt analytical ical methods methods:: Analytical Method Validation Protocol No.

Sr. No. Residue

Rinse

1

Active ingredient

2

Estimation of cleaning agent in final rinse/swab (as applicable)

3

Removal of solvent / solution used for  cleaning

8.2. 8.2.2 2

*Mat *Mater eria iall of of swab swab::

Swab

Nylo Nylon n mem membr bran ane e ffil ilte terr pap paper er / T Tex exwi wipe pe

Lot No. of the Swab used: *Note: Encircle whichever swab is appropria appropriate. te. 8.2 .2.3 .3

Vi Vis sual ual iins nspe pect ctiion of of cle cleaned ned co contact tact parts rts, ch chec ecke ked d by by

:

8.2.4

Visual iin nspection of of No Non-contact pa parts: ch checked by by

:

8.2.5

Time fr frame fo for st storage of of un unclean eq equipment (h (hours)

:

8.2.6 8.2 .6

Manufa Manufactu cturin ring g comple completed ted on :

at

8.2.7

Cleaning started on

:

at

8.2.8

Cleaning done by

:

 

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CLEANING OF EQUIPMENT

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Batch Number:

REFERENCE PROTOCOL PROTOCOL NO. : CVP 01, Version -

8.2.9

Concentra Concentration tion of the cleanin cleaning g agent, water water quality quality used used for cleaning cleaning and for for final rinsing rinsing,, volume of final rinse and hot water temperature temperature.. (if used) required for cleaning :

Cleaning agent and its concentration

Quality of water used for cleaning

Quality of water  used for final rinsing

Volume of  final rinse (kg)

If hot water is used, the temperature of  water (0C)

Ckd. by

Refer  attached sampling plan 8.2.10 Clean equipment equipment storage period after cleaning (days/hours): 8.2.11 Number of cleaning cycles performed: 8.3 Sr. No.

8.4

.

(for clean in place equipment). equipment).

Calibration : Equipment/ instrument

Code number  

Calibration done on

Calibration due on

Ckd. by

Precautions: Ensure that the Main Switch of the equipment is ‘OFF’ before commencement of cleaning. Checked By: .

 

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VALIDATION REPORT Date of Issue :

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Effective Date :

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Supersedes :

Page 5 of 13

Batch Number:

REFERENCE PROTOCOL PROTOCOL NO. : CVP 01, Version -

9.0

Validation Pr Procedure:

Note: Refer Cleaning Validation Protocol No: CVP01 Version No: Refer attached prerequisite checklist 1035-G-0038/A13 for calculations of limits for acceptance criteria.

10.1

ACCEPTANCE CRITERIA:

10.2 Limits of acceptance criteria for swab: Visually clean

LOD Limit for API

Swab (µg/ swab)

Dose criterion

10 ppm criterion

(µg / 4 inch2 / 16inch2)

(µg / 4 inch2 / 16inch2)

PDE criterion (µg / 4 inch2 / 16 inch2)

Most stringent limit from three criteria

10.3 Limits of acceptance criteria for rinse : LOD Limit for API rinse (ppm):

For the limits of acceptance criteria for rinse refer point no. 15.1. 10.4 Limits of acceptance criteria for cleaning agent rinse: LOD Limit for Cleaning agent rinse (ppm):

For the limits of 

acceptance criteria for rinse refer point no. 15.1. 11.0 11.0

Deta Detail ils s of of dev devia iati tion on / OOS OOS::

Deviation No./ report dated

12.0

OOS No./ Report dated

Type Type Of Vali Valida dati tio on:  

.

Checked by / Date

 

Location [

VALIDATION REPORT Date of Issue :

Report No.: CVR 01 Version No. :

CLEANING OF EQUIPMENT

Supersedes :

Batch Number:

Effective Date : Page 6 of 13

REFERENCE PROTOCOL PROTOCOL NO. : CVP 01, Version -

13.1

Frequency :

13.2 Concurren Concurrentt validation: validation: Three consecutiv consecutive e successful successful validatio validation n studies studies per equipment equipment based based on the worst case. 13.3 New Product Product as per per worst case case / new equipmen equipmentt / Change in cleani cleaning ng procedur procedure: e: Three successful validation studies per equipment. 13.4 In case any new new product product is introd introduced uced in facilit facility, y, Risk Risk assessmen assessmentt to be perform performed ed for  evaluation of worst case product for cleaning validation. if the product is identified to be a worst case three successful validation studies, If the product is not identified as worst case, then full cleaning validation validation will be performed for the first f irst batch. 13.5 Revalida Revalidation: tion: Revali Revalidati dation on shall shall be carried carried out in the followi following ng situation situations: s: 13 13.6 .6 Peri Period odic ic reval revalid idat atio ion: n: 13.5.1 For non-betalactum non-betalactum antibiotics and non-sexual hormones-corticosteroids: hormones-corticosteroids: one batch cleaning validation for each worst case product shall be done once in a year. 13 13.5 .5.2 .2 For othe otherr produc products: ts: 13.5.2.1 Perform an annual annual cleaning cleaning review report report and document document as per annexure annexure no. 1035-G1035-G0038/A14. Based on the review there could be one of the t he conclusion: conclusion: 1. The data review review definit definitely ely supports supports the conclus conclusion ion that the cleanin cleaning g process process is in a state of  control, and therefore is still validated. With such a conclusion, there is no need for protocol runs on any products within group. 2. The data data review review suggest suggests s that the cleanin cleaning g proce process ss may not be in a state of control control.. Perform one protocol run on the worst case product. If successful, the cleaning process is considered validated for all products in the group. For example but not limited to: An OOS is observed but there is insufficient evidence to prove that it is due to the previous product. 3. The data data review supports the the conclusion conclusion that that the cleaning cleaning process is is definitely definitely not in a state of control. Conduct an investigation to bring it into a state of control and then perform three protocol runs on the worst case product. For example but not limited to: An OOS is observed but there is sufficient evidence to prove that it is due to contamination from previous product. 13.5.2.2 Revalidation Revalidation shall be done for one one batch per worst case product in 5th year after the last successful run.

 

Location [

VALIDATION REPORT Date of Issue :

Report No.: CVR 01 Version No. : Supersedes :

CLEANING OF EQUIPMENT Batch Number:

Effective Date : Page 7 of 13

REFERENCE PROTOCOL PROTOCOL NO. : CVP 01, Version -

13 13.7 .7

Reva Revali lida dati tion on in in case case of chan change ges s in equi equipm pmen entt / produc productt conta contact ct part parts s / chang change e in sour source ce of  of   API, if required, based on impact assessment, cleaning procedure or cleaning aid (For  example: Cleaning agent) cleaning validation shall be initiated.

Note:

Revalidation Revalida tion to be carried out if the formulation of an existing cleaning agent is changed.

14.0

Risk management study : Risk Management Management Study document number :

.

 

ANNEXURE 1035-G-0038/A7 ANNEXURE (SPECIMEN COPY)

Location

VALIDATION REPORT Date of Issue :

Report No.: CVR 01 Version No. :

Effective Date :

CLEANING OF EQUIPMENT

Supersedes :

Page 7 of 13

Batch Number: REFERENCE PROTOCOL NO. : CVP 01, Version -

15.1 15.1

RE RESU SULT LTS S / OB OBSE SERV RVAT ATIO ION: N:

15.2

Rinses (for Active ingredient, cleaning agent and Solvent/Solution). A.R.Number: Equipment Part name/Rinse no.

1

Surface Area (inch2) (A)

Qty. of  rinse in Kg. (B)

Acceptance criteria in ppm

Content in ppm ppm from QC

Visual Done inspection by1 of  final rinse (Acceptance criteria : clear)

Ckd. by2

Content of  Cleaning Agent in Final Rinse / Swab Limit

Content

Solvent / Solution Content in final Rinse Limit

Checked By

Content

Prod Produc ucti tion on Of Offi fice cer; r; 2 Quality Assurance Officer 

(1035-G-0038/R1/4)

 

Location

VALIDATION REPORT Date of Issue :

Report No.: CVR 01 CLEANING OF EQUIPMENT

Version No. : Supersedes :

Effective Date : Page 8 of 13

Batch Number: REFERENCE PROTOCOL NO. : CVP 01, Version -

15.0 RESU RESULTS LTS / OBSERVA OBSERVATION: TION: (cont (continued inued...) ...)

Equipment Part name/Rinse no.

1

Surface Area (inch2) (A)

Qty. of  rinse in Kg. (B)

Acceptance criteria in ppm

Production Officer; 2 Quality Assurance Officer 

Content in ppm from QC

Visual Done inspection by1 of  final rinse (Acceptance criteria : clear)

Ckd. by2

Content of  Cleaning Agent in Final Rinse / Swab Limit

Content

Solvent / Solution Content in final Rinse Limit

Content

Checked By

 

ANNEXURE 1035-G-0038/A7 (SPECIMEN COPY)

Location

VALIDATION REPORT Date of Issue :

Report No.: CVR 01 Version No. : Supersedes :

CLEANING OF EQUIPMENT

Effective Date : Page 9 of 13

Batch Number: REFERENCE PROTOCOL NO. : CVP 01, Version -

15.2

Chemical Swabs (for Active ingredient) ingredient)  A. R. Number:

Equipment Part name

 Acceptance limit (mg / 4 inch 2 or 16 inch2)

Content in µg /swab (from QC)

Possible Contamination in next product (mgs/ 4 inch2 or 16 inch2) Cont nten ent tsminQC) µg) / swa wab b = Co (f (fro rom QC 1000

=

mg / 4 or 16 sq inch

(1035-G-0038/R1/4)

 

ANNEXURE 1035-G-0038/A7 (SPECIMEN COPY)

Location [

VALIDATION REPORT Date of Issue :

Report No.: CVR 01 Version No. : Supersedes :

CLEANING OF EQUIPMENT

Effective Date : Page 10 of 13 13

Batch Number:

REFERENCE PROTOCOL NO. : CVP 01, Version -

15.3

Microbial Swabs  A. R. Number :

Equipment Part name

Acceptance Limit Total Count Fungal Count (unit: ) (unit: )

Results Total Count Fungal Count (unit: ) (unit: )

15.4 Odour Verification Equipment parts including non contact parts as per the sampling plan

Acceptance criteria

Observation for Odour Verification

(1035-G-0038/R1/4)

 

Location [

VALIDATION REPORT Date of Issue :

Report No.: CVR 01 Version No. : Supersedes :

CLEANING OF EQUIPMENT Batch Number:

Effective Date : Page 11 of 13 13

REFERENCE PROTOCOL NO. : CVP 01, Version -

16. 6.1 1

Summ Summar ary y Of Of The The Vali Valida dati tion on Acti Activi vity ty::

16 16.2 .2

Base Based d on the the re resu sult lts s of swa swabs bs for for vari variou ous s part parts s of of the   (equipment/accessories), the carryover of (previous product) to next considered product product is found to be meeting / not meeting acceptance criteria.

16 16.3 .3

Base Based d on the the res resul ults ts of of final final rin rinse se for for var vario ious us par parts ts o off the   (equipment/accessories), the carryover of (previous product) to next considered product product is found to be meeting / not meeting acceptance criteria.

16 16.4 .4

Equipm Equipment ent part parts s on v visu isual al insp inspect ection ion foun found d : visua visuall lly y clean clean / not not clean clean ; meet meeting ing / not not meeting acceptance criteria

16 16.5 .5

Final Final rinse rinse of of equip equipmen mentt parts parts on visu visual al insp inspect ectio ion n found found clea clearr / not cle clear; ar; mee meetin ting g / not meeting acceptance criteria.

16 16.6 .6

Conte Content nt of clean cleanin ing g agent agent in fin final al rinse rinse/sw /swab ab of of equipm equipment ent part parts s fou found nd:: meetin meeting g / not meeting acceptance limit. (if applicable).

16 16.7 .7

Conte Content nt of sol solven ventt / soluti solution on iin n final final rrins inse e of equi equipme pment nt parts parts fou found: nd: mee meetin ting g / not meeting acceptance criteria. (if applicable). applicable).

16 16.8 .8

Count Count of fung fungii and and total total count count for for conta contact ct / non non cont contact act pa parts rts foun found: d: mee meetin ting g / not not meeting acceptance limit.

16 16.9 .9

Clean Cleanin ing g proced procedure ure that that consis consisten tently tly mee meetin ting/ g/ not not meeti meeting ng all all the the above above can be regarded as validated / Not validated.

17 17.0 .0

Recom Recomme menda ndatio tions ns (inclu (includin ding g requ require iremen ments ts of any additio additional nal docume documenta ntatio tion n/ changes to be made in cleaning sop):

 

Location [

VALIDATION REPORT Date of Issue :

Report No.: CVR 01 Version No. :

Effective Date :

CLEANING OF EQUIPMENT

Supersedes :

Page 12 of 13 13

Batch Number:

REFERENCE PROTOCOL NO. : CVP 01, Version -

18.0

Team approval:

Quality Assurance Date:

Production Date:

Quality Control Date:

19 19.0 .0

Review Review (inclu (inclusiv sive e of of ffoll ollow ow u up p acti action, on, if any): any):

20.0

Approved By :

Noted by :

Head Unit Quality Assurance Date: 21.0

Attachments

Document name:

Engineering Date:

Unit Head Date:

: Attachment No:

 

Location [

VALIDATION REPORT Date of Issue :

Report No.: CVR 01 Version No. : Supersedes :

CLEANING OF EQUIPMENT Batch Number:

Effective Date : Page 13 of 13 13

REFERENCE PROTOCOL NO. : CVP 01, Version -

22.0

Abbreviations µg  A.R.No. B. No. BW Ckd. by Inch2 Kg. LD50 LOD LOEL mg. No. NOEL NOAEL OOS PDE ppm QC Qty. SOP STV

: : : : : : : : : : : : : : : : : : : : : :

Microgram Analytical Reference Reference Number  Number  Batch Number   body weight of patient taking next product (50 kg) Checked by square inch Kilogram the the 50% 50% llet etha hall d dos ose e of of tthe he ta targ rget et resi residu due e in an anim animal al,, Limit Of Detection Lowest Observed Effect Level Milligram Number   No Observable Effect Level (of administration) No Observe adverse effect level Out of specification Permitted Daily Exposure Parts per million Quality Control Quantity Standard Operating Procedure Safe threshold value typically in mg / kg of body weight (by the appropriate route