document for the industry)

Sr no.

Generic Name Composition Parallel product

1 Beclomethasone Dipropionate 0.25 mg + Econazole 10 mg + Neomycin 5 mg per gm of

cream2 Beclomethasone dipropionate IP 0.025 % w/w

+ Neomycin sulphate IP 0.5 % w/w creamBeclomethasone Dipropionate IP 0.025 % w/w Neomycin sulphate IP 0.5 % w/wChlorocresol IP 0.1 % w/w In a cream base

Becto-NIndkus

2 Betamethasone 0.05 % + Miconazole 2 % cream

3 Betamethasone 0.5 mg + Calcipotriol 50 mcg ointment

4 Betamethasone Dipropionate 0.064% + Salicylic acid 3 % each ml lotion

5 Betamethasone dipropionate 0.064% + Gentamycin sulphate eq. to Gentamycin 1 mg per ml suspension lotion

6 Betamethasone Dipropionate eq to Betamethasone 0.5 mg + Butenafine Hcl 10 mg cream

7 Clindamycin Phosphate eq. to Clindamycin 10 mg + Adapalene 1 mg per gm Gel

Each Gram of Gel containsClindamycin PhosphateUS Peq. to Clindamycin 10 mg Adapalene 1 mgPreservativesMethyl Paraben IP 0.1 % w/wPhenoxyethanol BP 0.25 % w/w

FACECLIN-AAbbott

8 Clotrimazole 1 % + Framycetin sulphate 1 % + Dexamethasone 0.1 % creamClotrimazole 1 % + Halobetasol 0.05% cream

9 Eberconazole cream 1 %10 Econazole 10 mg + Beclomethasone

Dipropionate 0.25 mg + Neomycin 5 mg per gm of cream

11 Econazole nitrate cream 1 % 12 Halobetasol 0.05 % + Clotrimazole 1 % cream13 Halobetasol 0.05 % + Salicylic acid 6 %

ointmentHalobetasol Propionate USP 0.05 % w/wSalicylic Acid IP 6 % w/w Ointment base q.s.

HALOX ESRanbaxy

14 Halobetasol Propionate 0.5 mg + Salicylic acid 30 mg per gm of ointment

Halobetasol Propionate USP 0.05 % w/wSalicylic Acid IP 3 % w/w Ointment base q.s.

HALOX SRanbaxy

15 Halobetasol Propionate cream 0.05 % Halobetasol Propionate USP 0.05 % w/wOintment base q.s.

HALOX Ranbaxy

16 Miconazole 2 % + Betamethasone 0.05 % cream

17 Miconazole 20 mg + Halobetasol 0.5 mg per gram cream

18 Miconazole cream 2 %19 Mometasone 0.1 % + Fusidic acid 2 % cream/

ointment20 Mometasone furate USP 0.1 % + w/w +

Eberconazole 1 % w/w cream21 Mometasone Furoate 0.1 % + Nadifloxacin 1

% + miconazole nitrate 2 % creamEach gm of cream contains Nadifloxacin 10 mg

NADIMIXWockhart

Mometasone Furoate USP 1 mg Miconazole Nitrate IP 20 mgIn a cream basePreservativesMethylparaben IP 0.18 % w/wPropylparaben IP 0.02 % w/w

Neomycin Sulphate 500 mg + Clobetasol 500 mg cream

Each gm of cream containsClobetasol Propionate BP 0.05 % w/wNeomycin Sulphate IP 0.5 % w/wIn a non-greasy base

Tenovate GN GlaxoSmithKline

21 Mometasone Furoate (0.1% )+Tazarotene (0.05%) cream

22 Mometasone Furoate ( 1 mg /gm ) + Nadifloxacin ( 10 mg/gm) cream

23 Mometasone Furoate 0.1 % w/w + Terbinafine Hcl 1 % w/w cream

Mometasone Furoate IP 0.1 % w/w Terbinafine Hydrochloride BP 1 % w/w PreservativeChlorocresol IP 0.1 % w/wIn a cream base q.s.

Sebifin Plus Ranbaxy

24 Nadifloxacin 10 mg per gm + Mometasone furate 1 mg /gm cream

25 Nadifloxacin 10 mg + Miconazole 20 mg cream

26 Salicylic acid 6 % + Halobetasol 0.05 % ointment

Halobetasol Propionate USP 0.05 % w/vSalicylic Acid IP 3 % w/v Lotion base q.s.

HALOX SRanbaxy

27 Salicylic acid 30 mg + Halobetasol Propionate 0.5 mg per gm of ointment

28 Salicylic acid 3 % + Betamethasone Dipropionate 0.064 % each ml of lotion

29 Tretinion 0.025 % + Clindamycin 1 % topical gel

30 Tretinion 0.05 % + Hydrocortisone 1 % + Hydroquinone 2 % cream

31 Tretinion 0.05 % lotion32 Clindamycin Phosphate Gel USP Clindamycin Phosphate USP

Equivalent to Clindamycin 1 % w/wChlorocresol IP 0.12 % w/wIn a gel base q.s.

ACNESOL GELSystopic

Sr. no.

Generic Name

Composition

Parallel product

1 Calamine 15 % w/v +Zinc oxide 5 % w/v + Bentonite 3 % w/v + Glycerine 5 % w/v+ Sodium Citrate 0.05 % w/v lotion each ml contains

2 Calamine 8 % +Liquid paraffin 10 % lotion 3 Calcipotriol 50 mcg + Betamethasone 0.5 mg

ointment4 Calcipotriol gel 0.005 % ( additional dosage

form )5 Calcipotriol ointment 0.005 % + Clobetasol

Propionate 0.05 % ointment6 Camphor 4 % + Me –Salicylicate 30 % +

Menthol 10 % cream7 Camphor 4% w/w + S ( + ) Etodolac 5/10 w/w

+Menthol 10%w/w + Methyl Salicylate 5%w/w+ Linseed oil 3 % w/w

8 Chinoform 3 % + Beclomethasone Dipropionate 0.025 % ointment & cream

9 Chlorhexidine Gluconate 2 % + Silver Sulphadiazine 1 %+Lignocaine ( base ) 2 + cream

10 Clobetasol Propionate 0.05 % w/w + Ammonium Lactate 12 % w/w gel

11 Clobetasol Propionate 500 mcg + Nadifloxacin 10 mg each gram gel and cream

12 Clotrimazole 10 mg + Methyl-prednisolone Aceponate 1 mg / gm of cream

13 Clotrimazole 1 % + Halobetasol 0.05 % cream14 Diclofanoc Diethylamine 1.16 % w/w eq. to

Diclofonac Sodium 1 % w/w + Methylsalicylate , Linseed oil , Menthol

15 Eberconazole 1 % w/w + Mometasone Furoate USP 0.1 % w/w cream

Eberconazole NitrateEquivalent to Eberconazole 1 % w/w Mometasone Furoate IP 0.1 % w/w In a cream base

Ebernate-MDr.Reddys

16 Eberconazole cream 1 %17 Econzole 10 mg+ Beclomethasone Dipropionate

0.25 mg +Neomycin 5 mg per gm of cream18 Econazole Nitrate cream 1 %19 Erythromycin 2 % +Isotretinoin 0.05 % gel21 Fluconazole 2 % + Zinc pyrethione 1 %

suspension22 Fluconazole + Zinc Pyrethione each 30/60 ml

bottle contains ( 2 % + 1 %) lotion23 Fluconazole gel 0.5 %

24 Fluocinolone Acetonide 0.1 mg + Hydroquinone 20 mg +Tretinoin 0.25 mg per gm cream

25 Fusidic Acid 2 % + Mometasone 0.1 % cream / ointment

26 Fusidic Acid 2.0 % w/w + Halomethasone Monohydrate 0.5 % w/w cream

27 Halcinonide 1 mg + Neomycin Sulphate eq. to 2.5 mg of Neomycin base ointment / cream

29 Halobetasol Scalp approved 0.05% w/v30 Hydroquinone 2 % + Tretinoin 0.025 % w/w +

Mometasone 0.1 % gelHydroquinone USP 2 % w/wTretinoin USP 0.025 % w/w Mometasone Furoate IP 0.1 % w/wIn a cream base q.s.

SkinliteLiva

31 Hydroquinone 20 mg + Tretinoin 0.25 mg + Fluocinolone Acetoinide 0.1 mg per gm cream

Hydroquinone USP 2 % w/wTretinoin USP 0.025 % w/w Fluocinolone Acetonide IP0.01 % w/w In a cream base q.s.

Hyclean TFRanbaxy

32 Hydroquinone USP 2 % w/w + Tretinoin USP 0.025 % w/w + Allantoin USP 1 % w/w gel

33 Hydrous Benzoyl Peroxide eq. to Anhydrous Benzoyl Peroxide 2.5 % w/w + Clindamycin Phosphate eq. to Clindamycin 1 % w/w topical gel

34 Povidine Iodine 5 % + Sucralfate 7 % ointment35 Providone Iodine 50 mg + Sucralfate 70 mg +

Metronidazole 10 mg per gram of ointment36 Salicylic acid + Cetyl Alcohol + Stearyl Alcohol

(2 % + 20.65 % + 0.26 %) lotion37 Salicylic Acid + Coal Tar 3 % +

1 % solution39 Salicyclic Acid 50 mg + Methyl Prednisolone

Aceponate 1 mg ointment 40 Tazarotene 1 mg +Mmometasone Furoate 1 mg

per gram cream 41 Menthol 10 + Me-salicylate 30 % +Camphor 4

%cream 42 Menthol , Linseed oil, Methylsalicylate +

Diclofenac Diethylamine 1.16 % w/w eq to Diclofenac Sodium 1 % w/w

Diclofenac Diethylamine BP 1.16%w/w equivalent to Diclofenac Sodium 1.0 % w/wMethyl Salicylate IP 10.0 % w/wMenthol IP 5.0 % w/wCapsaicin USP 0.025 % w/wIn a cream base q.s.

SupamoveDr. Reddys

43 Me- Salicylate 30 % Menthol 10% + Camphor 4 % cream

45 Methylprenisolone Aceponate 1 m/gm + Clotrimazole 10 mg of cream

46 Miconazole 20 mg + Nadifloxacin 10 mg cream 47 Miconazole nitrate 2 % + Nadifloxacin 1 % +

Mometasone Furoate 0.1 % cream48 Mometasone 0.1 % + Hydroquinone 2 % +

Tretinoin 0.025 % w/w gel49 Miconazole Furoate 0.1 % + Nadifloxacin 1 % +

Miconazole Nitrate 2 %50 Nadifloxacin (10 mg/gm )+ Mometasone Furoate

(1 mg/gm) cream51 Mometasone furoate 0.1 % + Tazarotene 0.05 %

cream52 Nadifloxacin 10 mg + Clobetasol Propionate 500

mcg each gm and Gel53 Nadifloxacin cream54 Nadifloxacin gel 1 %

Clindamycin Phosphate Topical Solution USP Clindamycin Phosphate USP Equivalent to Clindamycin 1.0 % w/wIn a solution base q.s.

Acnesol 1 5 Systopic

List of additional products

Sr.No.

Generic Name Composition Market Product

1Beclomethasone dipropionate IP 0.025 % + Neomycin sulphate IP 0.5 % cream

Beclomethasone Dipropionate IP 0.025 % w/w Neomycin sulphate IP 0.5 % w/wChlorocresol IP 0.1 % w/w In a cream base

Becto-NIndkus

2Clindamycin Phosphate Topical Solution USP Clindamycin Phosphate USP

Equivalent to Clindamycin 1.0 % w/wIn a solution base q.s.


3Clindamycin Phosphate Gel USP Clindamycin Phosphate USP


ACNESOL GELSystopic

4Clindamycin Phosphate eq. to Clindamycin 10 mg + Adapalene 1 mg per gm Gel

Each Gram of Gel containsClindamycin Phosphate US Peq. to Clindamycin 10 mg Adapalene 1 mgPreservativesMethyl Paraben IP 0.1 % w/wPhenoxyethanol BP 0.25 % w/w

FACECLIN-AAbbott

5Menthol , Linseed oil, Methylsalicylate + Diclofenac Diethylamine 1.16 % w/w eq to Diclofenac Sodium 1 % w/w


SupamoveDr. Reddys

6Halobetasol 0.05 % + Salicylic acid 6 % ointment


HALOX ESRanbaxy

7Halobetasol Propionate 0.5 mg + Salicylic acid 30 mg per gm of ointment


HALOX SRanbaxy


Sr.No.


8Halobetasol Propionate cream 0.05 % Halobetasol Propionate USP 0.05 % w/w

Ointment base q.s.HALOX Ranbaxy

9Mometasone Furoate 0.1 % + Nadifloxacin 1 % + miconazole nitrate 2 % cream

Each gm of cream contains Nadifloxacin 10 mgMometasone Furoate USP 1 mg Miconazole Nitrate IP 20 mgIn a cream basePreservativesMethylparaben IP 0.18 % w/wPropylparaben IP 0.02 % w/w

NADIMIXWockhart

10





Sr.No.




9Hydroquinone 20 mg + Tretinoin 0.25 mg + Fluocinolone Acetoinide 0.1 mg per gm cream


Hyclean TFRanbaxy

10





Sr.No.


11

Mometasone Furoate 0.1 % w/w + Terbinafine Hcl 1 % w/w cream





Hyclean TFRanbaxy

13Eberconazole 1 % w/w + Mometasone Furoate USP 0.1 % w/w cream

Eberconazole NitrateEquivalent to Eberconazole 1 % w/w Mometasone Furoate IP 0.1 % w/w In a cream base

Ebernate-MDr.Reddys

14Hydroquinone 2 % + Tretinoin 0.025 % w/w + Mometasone 0.1 % gel

Hydroquinone USP 2 % w/wTretinoin USP 0.025 % w/w Mometasone Furoate IP 0.1 % w/wIn a cream base q.s.

SkinliteLiva

Sr.No.


1Beclomethasone dipropionate IP 0.025 % w/w + Neomycin sulphate IP 0.5 % w/w cream

Beclomethasone Dipropionate IP 0.025 % w/w Neomycin sulphate IP 0.5 % w/wChlorocresol IP 0.1 % w/w In a cream base

Becto-NIndkus

2Clindamycin Phosphate Topical Solution USP Clindamycin Phosphate USP

Equivalent to Clindamycin 1.0 % w/wIn a solution base q.s.


3Clindamycin Phosphate Gel USP Clindamycin Phosphate USP


ACNESOL GELSystopic

4Clindamycin Phosphate eq. to Clindamycin 10 mg + Adapalene 1 mg per gm Gel

Each Gram of Gel containsClindamycin Phosphate US Peq. to Clindamycin 10 mg Adapalene 1 mgPreservativesMethyl Paraben IP 0.1 % w/wPhenoxyethanol BP 0.25 % w/w

FACECLIN-AAbbott

5Menthol , Linseed oil, Methylsalicylate + Diclofenac Diethylamine 1.16 % w/w eq to Diclofenac Sodium 1 % w/w


SupamoveDr. Reddys

6Halobetasol 0.05 % + Salicylic acid 6 % ointment


HALOX ESRanbaxy

7Halobetasol Propionate 0.5 mg + Salicylic acid 30 mg per gm of ointment


HALOX SRanbaxy



9Mometasone Furoate 0.1 % + Nadifloxacin 1 % + miconazole nitrate 2 % cream

Each gm of cream contains Nadifloxacin 10 mgMometasone Furoate USP 1 mg Miconazole Nitrate IP 20 mgIn a cream basePreservativesMethylparaben IP 0.18 % w/wPropylparaben IP 0.02 % w/w

NADIMIXWockhart

10




11

Mometasone Furoate 0.1 % w/w + Terbinafine Hcl 1 % w/w cream





Hyclean TFRanbaxy

Eberconazole 1 % w/w + Mometasone Furoate Eberconazole Nitrate Ebernate-M

13 USP 0.1 % w/w cream Equivalent to Eberconazole 1 % w/w Mometasone Furoate IP 0.1 % w/w In a cream base

Dr.Reddys

14Hydroquinone 2 % + Tretinoin 0.025 % w/w + Mometasone 0.1 % gel

Hydroquinone USP 2 % w/wTretinoin USP 0.025 % w/w Mometasone Furoate IP 0.1 % w/wIn a cream base q.s.

SkinliteLiva

15

FDA/03/31/13 Date : 31/12/13To, The State Drugs Controller-cum-Controlling and Licensing Authority Food and Drug Administration, Haryana, SCO No.94, Sector-5, Panchkula

Sub. : Submission of documents as directed by your office.Ref. : Your letter No. Memo No8,. 1/108-2Drug-I-2013/9402 dated 12/12/13Respected Sir, With reference to your above said letter , we are hereby attaching following documents for your consideration.

1 ) Product list in triplicate with generic names2 ) Test procedures for all products arranged in sequence3 ) Reference to each product as cleared from New Drugs list arranged in sequence.

Thanking you.

Authorised Signatory

FDA/04/31/13 Date : 31/12/13To, The State Drugs Controller-cum-Controlling and Licensing Authority Food and Drug Administration, Haryana, SCO No.94, Sector-5, Panchkula

Sub. : Request to issue us “ Validity Certificate Respected Sir, We have applied for renewal of our manufacturing licence in Dec.2012. Renewal period applied for is from 01/01/2013 to 13/12/2017 .Our renewal is under process by your office. Sir, for our commercial purpose our clients ask for validity certificate .So we request you to kindly issue us validity certificate.Please oblige us.Thanking you.

Authorised Signatory

Design Layout & Operational Facilities for Sterile Products : Design Layout & Operational Facilities for Sterile Products Presented By Mr. Tausif R. Tamboli Under the guidance of Dr. Ashwini R. Madgulkar Co-guided by Mrs. Reshma Mirajkar Department of Pharmaceutics AISSMS’s, College of Pharmacy, Pune

Introduction : Introduction Part I of Schedule-M of Drugs & Cosmetics Act-1940 states the General requirements as Location and surroundings “The factory building(s) for manufacturer of the drug shall be so situated and shall have such measures as to avoid risk of contamination from external environment including open sewage, drain, public lavatory or any factory which produces disagreeable or obnoxious odour, fumes, excessive soot, dust, smoke, chemicals or biological emissions. Buildings and Premises The building(s) used for the factory shall be designed, constructed, adapted and maintained to suit the manufacturing operations so as to permit production of drugs under hygienic conditions. They shall conform to the conditions laid down by the Factories Act, 1948. Water system A validated system for treatment of water drawn from own or any other source to render it potable in accordance with standards specified by the Bureau of Indian Standards or Local Municipality, as the case may be, so as to produce Purified Water conforming to Pharmacopoeial specification. Disposal of waste The disposal of sewage and effluents

(solid, liquid & gas) from the manufactory shall be in conformity with the requirements of Environment Pollution Control Board. 2

Slide 3: Parenterals are sterile, pyrogen free preparations injected directly into internal body compartments through skin or mucous membrane. Classified as - Small volume parenterals Ampoules Vials - Large volume parenterals. 3

Slide 4: Sterility: ‘Sterility’ is an absolute term and indicates a state of freedom from all viable microorganisms. Free from microorganisms In practice no such absolute statement regarding absence of microorganisms can be proven Defined as the probability of 1 in a million of a container being contaminated (10-6) This referred to as the Sterility Assurance Level (SAL) It is not possible to measure “10-6” The required SAL can be achieved by applying a process that will reduce the number of organisms to zero and then apply a safety factor that will deliver an extra 6 log reduction. 4

Considerations in the processing of sterile pharmaceutical products : Considerations in the processing of sterile pharmaceutical products The design & layout of the manufacturing facility must be helpful in maintaining the quality, purity, identity and safety of the product being manufactured. Only trained personnel should be allowed to process these products. Sanitation and sterilization processes should be pre-validated. Use of laminar air flow equipments must be used. Particulate and microbial environment should be monitored as per the regulatory guidelines. Standard operating procedures should cover the issues related to people, materials, material flow, equipment, solution preparation, environmental monitoring and control. 5

Environmental control zone grouping (cGMP) : Environmental control zone grouping (cGMP) 6

Four classes of air cleanliness : Four classes of air cleanliness Class 100,000 : particle count not to exceed a total of 100,000 particles per cubic foot of size 0.5µ and larger or 700 particles per cubic foot of size 5.0µ and larger. Class 10,000 : particle count not to exceed a total or 10,000 particles per cubic foot of size 0.5µ and larger or 65-70 particles per cubic foot of a size 5.0µ and larger. Class 1,000 : particles count not to exceed a total of 1000 particles per cubic foot of size 0.5µ and larger or 10 particles per cubic foot of a size 5.0µ and larger. Class 100 : Particles count not to exceed a total of 100 particles per cubic foot of a size 0.5µ and larger. 7

Zones as per Gazette of India : Zones as per Gazette of India 8 WHITE

Ampoules : Ampoules Ampoules are single-dose sterile injectable product filled and sealed in the glass containers called ampoules. Planned capacity Bulk manufacturing: 450 Litres/8 hours Units: 1.5 Lakhs ampoules of 3 ml each Manpower Requirement: 30 persons Assumption- Mfg. of bulk and filtration is one area with facility to manufacture 450 Lit. Of injection bulk in one batch. Filling/Sealing and packing two lines of 7500 ampoules capacity per 8 hours each. 9

Slide 10: Detailed Flow Diagram (Mfg Process) 10 Receiving & Weighing of Raw materials Solution Preparation Solution Filtration Ampoule arranging Ampoule washing Ampoule drying / Sterilization Ampoule filling & Sealing Sterilization Visual inspection Good ampoules Rejected ampoules Labelling Recovery & Filtration Packing Reprocessing Leak Test Pyrogen Test pH Fill volume check Leak test Size of filter Rate of filtration Filter integrity test

Work Station Listing : Work Station Listing Product / Process related activities Day Stores Solution preparation Solution filtration Ampoule washing, Sterilization & Depyrogenation Ampoule filling and sealing Ampoule inspection Ampoule Labeling & Packaging Recovery Support Activities Inprocess Storage Area Process Area Change Room (Aseptic) House Keeping material Storage Drinking water, Urinal / Toilets Office & Documentation Room Consumable Store Laundry for Sterile Garments Tool Room Maintenance Room 11

Area and Activity Listing :

Area and Activity Listing 12

Capacity Planning : Capacity Planning Small scale Unit capacity: 1.0 Lakh ampoules of 3 ml each per shift Bulk capacity: 300 Lit. per shift 1 line of 1 Lakh each Medium scale Unit capacity: 2.0 Lakh ampoules of 3 ml each per shift Bulk capacity: 600 Lit. per shift 2 lines of 1 Lakh each Large scale Unit capacity: 3.0 Lakh ampoules of 3 ml each per shift Bulk capacity: 900 Lit. per shift 3 lines of 1 Lakh each 13

Equipment Details : Equipment Details Weighing balances Manufacturing vessels for solution preparation for ampoules Filter presses Ampoule washing machine Tunnel sterilizers Autoclave Dry heat sterilizer Ampoule filling & sealing machine Ampoule inspection machine Ampoule labeling machine Conveyer belts Box Strapping machine 14

Capacity & Dimensions : Capacity & Dimensions 15

Calculations of Manpower Required : Calculations of Manpower Required 16

Workstation & Section Layouts : Workstation & Section Layouts Day Stores Day store is needed for the following purposes Storage of empty ampoules Storage of raw materials Storage of secondary packaging materials Solution Preparation Room Pharmaceutical Aspects Drug & other ingredients are dissolved in the desired vehicle (usually WFI) A mixing tank (jacketed) is used for heating & cooling purposes Parameters considered: Addition of ingredients, Rate of mixing, pH adjustment Design Aspects Separate entry should be provided for materials & personnel entering into this room (Glass / Aluminium partition). Personnel entry should have a provision for wearing an additional process gown. Material entry should have sufficient provision for keeping raw materials (other than WFI). SPA should have provision for keeping mfg. Vessels & connection of the required utilities like WFI, purified water, steam, compressed air, nitrogen gas, etc. Sufficient space should be provided for movement of people in the area. 17

Layout of Solution Preparation Room : Layout of Solution Preparation Room 18 Solution Preparation Vessel Solution passing stainless tube

Solution filtration & Storage Room : Solution filtration & Storage Room Pharmaceutical Aspects Pore size of filter and types of bacteria removed 19

Slide 20: Design Aspects Solution filtration area is adjacent to solution preparation area. This is an aseptic area. The prepared solution is passed by air or Nitrogen gas pressure from the mfg. vessel to the filtration unit. The filtration area should have provision for both carrying out filtration & storing filtered solution. 20 Material Hatch (1 x 1 m) Solution Filtration Room Filter press Solution receiving stainless steel tube Filtered solution storage room

Ampoules Washing, Drying & Depyrogenation Room : Ampoules Washing, Drying & Depyrogenation Room Empty ampoules are received in fibre board boxes. It is needed to provide decartoning room adjacent to washing area. A vacuum is applied to suck particles from ampoules using vacuum cleaner. The ampoules are automatically conveyed, in an inverted position, through a series of treatments with hot detergent, hot purified water & final rinse with WFI. The ampoule washing machine is directly attached to sterilizing & depyrogenating tunnel. 21 Decartoning room (3 x 3 m) Turn table (1 x 1 m) Washing machine (3 x 3 m) Sterilization tunnel (2 x 5 m)

Ampoule filling & sealing room : Ampoule filling & sealing room This room is adjacent to sterilizing tunnel. The washed and sterilized ampoules in cool condition are received on a turn table in ampoule filling / sealing room. After filtration of liquid, it is subdivided from bulk container into individual dose container ampoules. A measured volume of liquid is forced into the constricted opening of the ampoule through the orifice of the delivery tube. The delivery is obtained from the stroke of the plunger of a syringe. Filling process must be carried out under aseptic conditions (Class 100 area). Ampoules are sealed by melting a portion of the glass of the neck in a high temperature gas-oxygen flame. The filled and sealed ampoules are collected in S.S trays

of suitable size & transferred to the leak testing room. An ampoule filling machine upto 8 head given about 250-300 ampoules per min. leading to an output of about 1 Lakh amp./shift. This machine may be acomodated in about 2 x 2 m space. 22

Layout of ampoule filling & sealing room : Layout of ampoule filling & sealing room 23 Ampoule filling m/c (2 x 2 m) Turn table (1x1 m) Ampoule filling room (5 x 5 m)

Ampoule Inspection Room : Ampoule Inspection Room Visual inspection is carried out for particulate evaluation. Each filled unit is subjected individually to a visual inspection & the unit with visible particles should be discarded. All the product units from a production line are inspected individually by human inspectors under a good light baffled against reflection into the eye and against a Black & White background. An Ampoule Inspection Room should have an arrangement for storage of unchecked units, inspected units and rejected units. Space for automated equipments & seating arrangement for the inspection employees (manual). The automated unit occupies about 1 x 2 m space and before this a space of about 1 x 1 m for turntable may be required. Space for movement of personnel working in visual inspection section. 24

Layout of Ampoule Inspection Room : Layout of Ampoule Inspection Room 25 Ampoule inspection machine (2 x 1.5 m) Turn table (1x1 m) Ampoule inspection room (5 x 5 m)

Ampoule Labeling & Packaging Room : Ampoule Labeling & Packaging Room Labeling designates all labels and other written, printed or graphic matter upon an immediate container, or upon, or in any package or wrapper in which it is enclosed with the exception of outer shipping container. Inspected ampoules are fed through a turn table (1 x 1 m) to the labeling machine (2 x 1.5 m). Turn table passes the inspected units to the labeling machine. The labeling machine labels the units & directly delivers the labelled unit on the conveyer belt (4-5 m long & 1 m wide) for secondary & tertiary packaging. A box strapping machine(1 x 1 m space) is present at the end of the conveyer belt. The finished packs in the shippers are then stacked on the pallet at the end of the belt & then periodically transferred to the finished goods ware house. 26

Layout of ampoule labeling & packaging machine : Layout of ampoule labeling & packaging machine 27 Ampoule labeling machine (2 x 2 m) Turn table (1x1 m) Ampoule labeling & packaging room (5 x 5 m) Conveyer belt (1 x 4 m) Box strapping machine (1 x 1 m)

Recovery Room : Recovery Room Rejected ampoules are many a times crushed and the solution is recovered by proper filtration system consisting of coarse primary filtration through S.S sieve type filter to remove bigger glass particles and then through 0.22 μ filter. Design Aspects: Storage for rejected ampoules for recovery (1 x 2 m). Storage for broken ampoules (1 x 1 m). Filtration unit (1 x 1 m). Storage for filtered solution. Ampoule crushing machine (1 x 1 m). 28

Slide 29: 29 Store Rack (2 x 1 m) Ampoule crushing machine (1 x 1 m) Filter press (0.5 x 0.5 m) Filtered Solution Room Broken glass storage (0.5 x 0.5 m) 5 m 3 m Recovery Room

In process storage area : In process storage area Filtered bulk solution ready for filling. This area should be provided in the aseptic area only as a part of sterile filtration & storage area. Filled & sealed ampoules & vials. Rejected ampoules & vials. Inspected good ampoules & vials. 30

Aseptic Process area change room : Aseptic Process area change room A specially designed change room for entering into aseptic operations area, and exit from it. Change room leading into Class A & B environment should be designed as air-lock vestibules. There should be physical separation of the different stages of changing to minimize microbial & particulate contamination. All the changing rooms should be properly flushed effectively with properly filtered air. The final stage of the changing room should be of the same grade as the area into which it leads. The use of separate changing rooms for entering & leaving clean areas is desirable. 31

Aseptic Process area change room :

Aseptic Process area change room 32 Room no.1: Remove Factory Uniform & keep in a double cupboard. Wash your hands & dry them. Room no. 2: Put on sterilized uniform Room no. 3: Disinfect hands, put on gloves, disinfect gloves. Confirm in mirror that you have put your uniform correctly and then enter the processing area. Room no. 4: Come back in the 4th room for exit. Room no. 5: Remove your sterile garments & discard them for rewashing & sterilization purpose. Room no. 6: Take out your factory uniform and wear it & come out to the corridor. 6 m 4 m

Slide 33: 33 10 12 13 14 15 16 17 18 19 20 24 25 26 27 Change Room [8x5] Office [5x3] Ampoule Recovery Room [5x2] Day Store (R.M) [5x3] Day Store (empty ampoules) [5x3] House keeping & material store [5x3] Consumables store [5x3] Garment wash [5x6] Equipment wash [5x3] Preparation & Sterilization Room [10x10] Preparation Room [] Solution Preparation Room [4x2] Material Entry [4x2] Men entry [2x2] Decartoning Rooms [3x3] Decartoning Rooms [3x3] Ampoule washing machines [2x2] Ampoule washing machines [2x2] Sterilizing tunnel [2x4] Sterilizing tunnel [2x4] Ampoule filling / Sealing room [6x6] Ampoule filling / Sealing room [6x6] Filtered Solution Store room [6x6] Filtration Room [3x6] Autoclave [2x3] Dry Heat Sterilizer [] Hot Room [8x10] Aseptic Change Room [6x4] Rejected Ampoule Store [4x5] Store for inspected Good Ampoules [8x5] Visual Inspection Room [8x5] Filled uninspected Room [5x5] Filled Ampoules Exit [3x5] Label / Carton store [4x6] Secondary Packaging Store [6x6] Packaging lines [5x14] Packaging lines [5x14] Temporary store for finished goods

Vials : Vials Vials are multi-dose sterile injectable product filled in a small glass container called vial & sealed normally using a rubber plug and aluminium seal or a similar packaging system. Vials contain liquid as well as dry sterile powder 34

Work Station Listing (Liquid & Dry sterile powder vials) : Work Station Listing (Liquid & Dry sterile powder vials) Product / Process related activities Day Stores Solution preparation (liquid) Solution filtration (liquid) Vial washing, Sterilization & Depyrogenation Rubber plug washing, unit preparation & sterilization Vial filling and sealing Vial inspection Vial Labeling & Packaging Recovery Support Activities Inprocess Storage Area Process Area Change Room (Aseptic) House Keeping material Storage Drinking water, Urinal / Toilets Office & Documentation Room Consumable Store Laundry for Sterile Garments Tool Room Maintenance Room 35

Slide 36: 36 Detailed Flow Diagram for Mfg. Process of vials (Liquid)

Slide 37: 37 Manufacturing process for vials (Dry powder)

Slide 38: 38

Slide 39: 39 Area and Activity Listing (Liquid)

Slide 40: 40 Area and Activity Listing (Sterile Dry Powder)

Calculations of Manpower Required : Calculations of Manpower Required 41

Rubber plugs, seals washing, sterilization & unit preparation room : Rubber plugs, seals washing, sterilization & unit preparation room Rubber plugs are required to be cleaned by washing with detergent & purified water & finally rinsed with WFI. Cleaned rubber plugs are sterilized by autoclaving & used as such for liquid vials or dried in case of dry powder vials. Aluminium seals are cleaned & sterilized using 70 % isopropanol. This area should include following provisions: Autoclave Dry Heat Sterilizer Unit Preparation Room Plugs/seals washing, sterilization room. 42

Slide 43: 43 Unit Preparation Room Plug/seal wash room (3x3 m) Autoclave Oven Preparation & sterilization area (2 x 2 m) Hot Room 8 m 17 m Layout of Preparation & Sterilization area

Vial filling & sealing room :

Vial filling & sealing room This room is adjacent to sterilizing tunnel. The washed & sterilized vials in cooled condition are received on a turn table in the vial filling/sealing room. The turn table directs the vials to the filling & plugging machine. The filled & plugged vials are transferred to cap sealing machine. Sealed vials are collected in S.S trays & transferred for leak testing & sterilization (if required). The filling & plugging area in separated by a partition from cap sealing area. Sufficient space for movement of personnel. Turn table occupies a space about 1 x 1 m. Space occupied by filling & plugging m/c is about 3 x 5 m & cap sealing m/c is about 1.5 m x 1.5 m. 44

Slide 45: 45 45 Vial filling m/c (2 x 3 m) Turn table (1x1 m) Vial filling/sealing room (5 x 5 m) Vial sealing m/c 1 x 1.5 m

References : References Pharmaceutical Facilities: Design, Layouts and Validation, Manohar A. Potdar, 2010, PharmaMed Press, Hyderabad, Page no. 193-233 Pharmaceutical Quality Assurance, Manohar A. Potdar, 2nd Edition, 2007, Nirali Prakashan, Pune, Page no. 13.1-13.10 Forensic Pharmacy, Dr. B.S. Kuchekar, Mr. A. M. Khadatare and Mr. S. C. Itkar, 7th Edition, 2007, Nirali Prakashan, Pune, Page no. 5.165, 5.166 Pharmaceutical Dosage Forms: Parenteral Medications, Vol. 2, 2nd Edition,1993, Marcel Dekker, Inc., New York, Page no. 317-366 http://www.google.co.in/images/baxter+facility+layout.jpg Theory and Practice of Industrial Pharmacy, Leon Lachman, Herbert A. Liberman, Joseph L. Kanig, 3rd Edition, Varghese Publishing House, Dadar, Mumbai, Page no. 639-675 46

Slide 47: 47

LAYOUT AND DESIGN OF FACILITIES & MATERIAL FLOW: LAYOUT AND DESIGN OF FACILITIES & MATERIAL FLOW Presented By: Sumit Kumar Mittal M.Pharma (II Sem ) Department of Quality Assurance I.S.F College of Pharmacy, Moga (Punjab) 1

PowerPoint Presentation: (A) Layout of the facilities (B) Control of cross contamination (C) Humidity/temperature controls (D) Water systems (E) Plant pest control 2

PowerPoint Presentation: (A) Layout of the facilities : (Material Flow) The overall facility as well as the individual process areas should always take into consideration the most simplistic route of material flow and the control of cross contamination. The prime objective at all stages of inventory is to separate released materials from quarantined or rejected materials. The 3 typical layouts for pharmaceutical manufacturing are as follows : Perimeter manufacturing, center warehouse. Circular flow. Straight line flow. 3

PowerPoint Presentation: It is one of the more popular solid-dosage form layouts. It involves the following : The center of the facility is a storage of warehouse area for raw materials, packaging components and bulk stocks, with the manufacturing and packaging operations located at the outer perimeter. Flow of raw materials : Receiving and approved dispensing manufacturing Quarantine areas storage area packaging tablets in quarantine bulk stock Packaging is scheduled tablets and packaging component delivered from bulk stock and approved storage areas 4

Advantage :: Advantage : It has the advantage of space conservation by virtue of having the supply areas close to the areas being supplied. Disadvantage : A significant disadvantage is the crossover traffic pattern of materials , with the ensuing potential for contamination or mix-up. 5

PowerPoint Presentation: 6

PowerPoint Presentation: Receiving area, Approved raw materials, & Component storage. Manufacturing, Quarantine, Bulk stock, & Packaging area. This is the second layout consisting of 2 sides across a central corridor. The movement of materials from one area to another is the same as in the 1 st layout. 7

Advantage : : Advantage : Owing to the modified layout, the flow is basically circular, eliminating much of the crossover traffic present in the 1 st layout. Disadvantage : Though much of the crossover traffic is eliminated, chances of contamination are still significant enough. 8


PowerPoint Presentation: It consists of a basic straight line flow to minimize contamination or mix-up, moving the materials along a critical path. Advantage : The principal advantage over the layouts is minimal cross-over of materials , thus minimizing the potential for contamination or mix-up. Disadvantage : One disadvantage is the additional space required to accommodate this configuration. 10


(B) Control of cross contamination :: (B) Control of cross contamination : Air handling systems : It is one of the most important considerations in the design of a solid dosage form. The C-GMP regulation 211.46 section c specifically mandates that : “ Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas. In areas where air contamination occurs during production, there shall be adequate exhaust systems or other systems adequate to control contaminants.” 12

PowerPoint Presentation: Dust collection : Sampling and weighing 13

PowerPoint Presentation: The first area that must be addressed is the raw material sampling rooms and the pharmacy or dispensing area. The area should be an enclosed facility with separate booths or hoods where the individual weighing or sampling can take place. These areas may be designed using horizontal laminar flow or appropriate hoods and other dust pick up devices. The supply air to these stations will, therefore, either be HEPA filtered at the pick up stations or HEPA filtered after the dust collection prior to returning to the general area or supply air. 14

PowerPoint Presentation: Granulating : There are 2 basic methods of air system design. In the following illustration, the mixing rooms are negative to the main corridor. This prevents air borne particles from escaping into the main area and migrating to the other rooms. 15


PowerPoint Presentation: Compression : The following figures illustrate a tablet compression room design using slightly negative pressure in the corridors to preclude contamination of other booths through open doorways. Both

methods, designed and maintained properly, will work equally as well. The important point being the supply air is pre-filtered through a dust collector and final filtered through a HEPA filter. 17



PowerPoint Presentation: Packaging : Some tablet-filling machines are designed with a self-contained vacuum system that returns the air, filtered through an absolute filter, back to the packaging area. If the filling machine being used does not have an air filtering system, dust pick-ups of approximately 300 CFM should be provided at the hopper station and 50 CFM at the bottle chute. 20

(C) Humidity/temperature controls :: (C) Humidity/temperature controls : From the standpoint of both product protection and employee comfort, careful consideration must be given to humidity and/or temperature controls. Unless otherwise indicated, conditions of 45% R.H. and 70⁰ F are generally adequate for critical manufacturing areas such as compression and coating. The ventilation could be provided by large roof fans to circulate air. In addition, some form of supplemental air heating, such as hot-air blowers, should be provided for cold areas, such as shipping or receiving docks. 21

(D) Water systems : : (D) Water systems : CGMP regulation 211.48 states : “that the supply of potable water in a plumbing system must be free of defects that could contribute contamination to any drug product.” The USP XXI defines purified water, USP, as water obtained by process such as ion-exchange treatment, reverse osmosis, distillation, electro dialysis and ultra filtration or other suitable processes. Classes of water normally encountered are : 1.Well water, 2.Potable water, USP. 3.Purified water , USP. 4.Specially purified grades of water, such as water for injection, USP, or 5. FDA water for cleaning and initial rinse in parenteral areas. 22

PowerPoint Presentation: 1. Well water : It is the water drawn directly from a well. The water may not be either chemically or microbiologically pure because it is untreated. 2. Potable water : It is city water or private well water that has usually been subjected to some form of microbiological treatment, such as chlorination, to meet the US public health services standard with respect to microbiological purity. 3. Purified water : It is usually prepared from water that meets the potable water standard. Purified water is treated to attain specified levels of chemical purity and it is the type of water used in most p’ceutical processing operations. 23

PowerPoint Presentation: Water treatment equipment : De-ionization equipment should be sized to ensure frequent regeneration and a re-circulating system should be installed on the unit that approaches the rated flow of the de-ionization unit. Water filtration : It is approached on the basis of 2 major considerations : Prefiltering : To prevent large particulates from entering the system. The prefilters are generally the replaceable cartridge type with porosities ranging as high as 25 µ . Micro filtering : To remove bacteria . Micro filtering is usually accomplished with a 0.2 µ absolute filters, which will remove most bacteria. 24

PowerPoint Presentation: Sanitization procedures : It is best accomplished through several methods. After periods of low usage of water, the system should be flushed with a supply of water that has residual chlorine. Periodic hyper chlorination also is recommended. Effective microbial control can be maintained by storing water at 80⁰c. U.V. radiation may be used, but it has limited application because of the many factors which can reduce it’s effectiveness. 25

(E) Plant pest control :: (E) Plant pest control : The CGMP regulation 211.56(a) states that : “Any building used in the manufacture, processing, packing or holding of a drug product shall be maintained in a clean and sanitary condition. Any such building shall be free of infestation by rodents, birds, insects and other vermin. Trash and organic waste matter shall be held and disposed of in a timely and sanitary manner.” A pest control program should be developed that will ensure the integrity and quality of products produced and comply with existing legislation. The program should contain a list of approved pesticides to be used in the plant. Individual sheets should be prepared for each specific item of use. 26

PowerPoint Presentation: Basic information should be spelled as follows : Classification. Type of action. Chemical name and concentration of active ingredient. Effective for : To be used for : Area of usage. Trade name of the pesticide. Mode and frequency of application. Toxicities and any specific toxic symptoms, if known. Status of government approval. Specific restrictions and cautions. 27

PowerPoint Presentation: The development of sheets will serve a 2 twofold purposes : The sheets can be subjected to approval by the plant safety organization to determine if the materials comply with the Occupational safety and Health administration (OSHA) requirements and the requirements of other state or local agencies. The sheets would also facilitate compliance with the CGMP regulation 211.56 (c). Written records of regularly scheduled inspections and preventive treatments should be maintained. Emergency or special services should be documented specifying : The type of problem encountered, The service rendered, Effectiveness of the treatment, & Any follow up that might be required. 28

PowerPoint Presentation: The program should also specify when production interruptions might be necessary , either due to the presence of a specific pest or to avoid possible contamination during the treatment to exterminate a pest. All manufacturing areas should be constructed using non porous materials on the walls of the floors. Any protrusions such as pipes and electrical walls should be minimized . Spacing should be allocated carefully to provide sufficient rooms for all operations. There should be adequate lightning and the areas should be remote from any openings to the outside . Care should be taken that adequate training in understanding CGMPs be given to all personnel. Outside contractors must also be trained and understand CGMPs before embarking any construction or remodeling efforts having to do pharmaceutical manufacturing. 29

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