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SCHEDULE M“Good Manufacturing Practices”

Presented By,RASIKA WALUNJM.PHARM (QAT)

Modern College Of Pharmacy (For Ladies), Moshi Pune

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Content • What is schedule M • Contents1. General 2. Building and Civil Works3. Air Handling System (Central Air-Conditioning)4. Environmental Monitoring5. Garments6. Sanitation7. Equipment8. Water and Steam Systems9. Manufacturing Process10. Product Containers and Closures• Specifications• Master Formula Records

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What is schedule “M”……???Schedule M is a part of Drug and Cosmetic act 1940. It is

GMP for pharmaceuticals that should be followed by pharmaceutical manufacturing units in India.

It is a part of a quality assurance which ensures that the products are consistently manufactured and controlled to the Quality standards appropriate to their intended use.

GMP" - A set of principles and procedures which, when followed by manufacturers for therapeutic goods, helps ensure that the products manufactured will have the required quality.

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Continue …

Schedule “M” Requirement of factory premises, plant and

equipments for pharmaceutical products,

M-1 Requirement of factory premises for manufacturing of

homeopathic preparations,

M-2 Requirement of factory premises for manufacturing of

cosmetics,

M-3 Requirement of factory premises for manufacturing of

medical devices

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Parts of schedule “M”

Part I:Good Manufacturing Practices for premises and materials

Part II: Good manufacturing practices for Specific Requirements of plant and Equipment

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Part I:Good Manufacturing Practices for premises and materials

PART I(A) - Specific Requirements for manufacturing sterile products,

SVPs & LVPs and sterile ophthalmic Preparations.

PART I (B) - Specific requirement for Manufacture of oral Solid Dosage

Forms (Tablet and capsule).

PART I (C) - special requirement for manufacture of oral liquids (syrup,

elixir, emulsion and suspension).

PART I (D) - Manufacture of External Preparation (Creams, Ointment,

Paste, Emulsion, Lotion, solution, Dusting Powder and dental Products).

PART I (E) - Specific requirements for manufacturing of metered dose

inhalers.

Part I (F) - Specific requirement of premises, plant and material for

manufacture of bulk drugs.

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Specifications should be made for…

For raw materials and packaging materials.

For product containers and closures.

For in-process and bulk products.

For finished products.

For preparation of containers and closures.

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Part-I GMP for premises and materials

General Requirement Location and Surroundings Buildings and premises, Water system Disposal of waste Warehousing area Production area Ancillary areas Quality control area Personnel

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….Continue Health ,Clothing and sanitation of workersManufacturing operation and Control (precaution against

mix-up and cross- contamination) Sanitation in the manufacturing premises • Raw material Equipment • Documentation and Records • Labels and other printed material • Quality assurance Self inspection • Quality audit • Quality control system

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….Continue Specifications i. For raw materials and packaging materials. ii. For product containers

and closures. ii. For in-process and bulk products. iii. For finished products. iv. For preparation of containers and closures. Master Formula Records

There shall be master formula records relating to all manufacturing

procedures formula shall include: -

(a) The name of the product together with product reference code.

(b) The patent or proprietary name of the product along with the generic

name, size.

(c) Name, quantity, and reference number of all the starting materials to be

used.

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…Continue (d) a statement of the processing location, (e) the methods, or reference to the methods, equipment's including cleaning, assembling, calibrating, sterilizing, (f) detailed stepwise processing instructions,(g) the instructions for in-process control(h) the requirements for storage conditions of the products( i ) packing details and specimen label.Packing Records These shall include a. name of the productb. description of the dosage formc. the pack size d. complete list of all the packaging materialse. description of the packaging operationsf. details of in-process controls

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….Continue Batch Packaging Records Batch Processing Records Standard Operating Procedures (SOPs) and Records, regarding a. Receipt of materials b. Sampling c. Batch Numbering d. Testing e. Records of Analysis f. Reference Samples g. Reprocessing h. Recoveries Distribution records i. Validation and process validationj. Product Recalls k. Complaints and Adverse Reactions

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Site Master File 1) General information, 2) Personnel 3) Premises 4) Equipment's5) Sanitation .6) Documentation 7) Production8) Quality Control.9) Loan licence manufacture and licensee 10) Distribution, complaints and product recall. 11) Self inspection12) Export of drugs.

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PART I (A) Requirement for Manufacture of sterile products SVPs & LVPs and Ophthalmic

Premises

1. Aseptic Area 2. Air handling System (Central Air- Conditioning)

3. Environmental monitoring 4. Garments 5. Sanitation 6. Equipment 7. Manufacturing processes 8. Sterilization 9. Documentation

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Air handling system Air Handling Units for sterile product manufacturing areas shall

be different from those for other areas.

Critical areas, such as the aseptic filling area, sterilized components

unloading area and change room conforming to Grades B, C and D

respectively shall have separate air handling units.

The filling, manufacture, filter configuration, and terminal

sterilization in the air handling system shall be suitably designed to

achieve the Grade of air.

Unless there are product specific requirements, temperature and

humidity in the aseptic areas shall not exceed 27°C and relative

humidity 55%, respectively

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Airborne Particulate Classification For ManufactureOf Sterile Products

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Types Of Operations To Be Carried Out In The Various

Grades For Terminally Sterilized Products

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Environmental monitoring All environmental parameters shall be verified and established at the time of

installation and thereafter monitored at periodic intervals and recorded.

The recommended frequencies of periodic monitoring shall be as follows :-

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Garments

Only clean, sterilized and protective garments shall be used at each

work session where aseptic filtration and filling operations are

undertaken.

The garments shall be made of non-shedding and tight weave

material. Cotton garments shall not be used.

Garments shall be single piece with fastenings at cuffs, neck and at legs

to ensure close fit. Footwear should be suitably plastic or rubber material and cleaned

with bactericide. Safety goggles and numbered glass should be sanitized.

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Sanitation

This includes written procedures for sanitation which is performed by

trained employee.

Distilled water acquired from plant at 70°C or alcohol or isopropyl

alcohol may be used in dilution of disinfectant.

Diluted disinfectants shall bear the label “use before”, based on

microbiological establishment of the germicidal properties.

The solutions shall be adequately labeled and documents maintained

Formaldehyde may be used normally for fumigation of aseptic area.

Cleaning of sterile processing facilities shall be undertaken with air suction

devices or with non-linting sponges or clothes.

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Equipment

The special equipment required for manufacturing sterile products

includes component washing machines, steam sterilizers, dry heat

sterilizers, membrane filter assemblies, manufacturing vessels,

blenders, liquid filling machines, powder filling machines, sealing

and labeling machines, vacuum testing chambers, inspection

machines, lyophilisers, pressure vessels etc. may be provided with

SOP, depending upon the type and volume of activity.

The construction material used - stainless steel 316 or Boro-silicate

glass (if glass containers) and the tubing shall be capable of being

washed and autoclaved.

Installation qualification should be performed.

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Manufacturing process

Manufacture of sterile products shall be carried out only in areas under

defined conditions.

Gases coming in contact with the sterile product shall be filtered through two

0.22 µ hydrophobic filters connected in-series.

Each lot of finished product shall be filled in one continuous operation. In

each case, where one batch is filled in using more than one operation, each lot

shall be tested separately for sterility and held separately till sterility test

results are known.

Special care shall be exercised while filling products in powder form so as

not to contaminate the environment during transfer of powder to filling

machine-hopper.

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Terminally sterilized products. Preparation of primary packaging material such as glass bottles,

ampoules and rubber stoppers shall be done in at least Grade D

environment.

All the process used for component preparation shall be validated.

Filling of products requiring terminal sterilization shall be done under

Grade A environment with a Grade C background.

Preparation of solutions, which are to be sterilized by filtration, shall be

done in Grade C environment, and

The preparation of materials and products shall be in a Grade A

environment with Grade B in background.

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Documentation

The manufacturing records relating to manufacture of sterile products shall indicate the following details:-

(1) Serial number of the Batch Manufacturing Record.(2) Name of the product(3) Reference to Master Formula Record.(4) Batch/Lot number(5) Batch/Lot size.(6) Date of commencement of manufacture and date of completion of manufacture.(7) Date of manufacture and assigned date of expiry.(8) Date of each step in manufacturing.(9) Names of all ingredients with the grade given by the quality control

department.(10) Quality of all ingredients.

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PART I (B) Specific Requirements for manufacture of oral solid dosage form

1. General Requirements 2. Sifting, 3. Mixing and granulation 4. Tablet compression 5. Tablet coating Filling of hard gelatine capsule

Printing of tablet and capsule 6. Packaging (strip or blister)

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PART I (C) Specific Requirements for manufacture of oral liquid dosage form (Syrup, Elixir, Emulsion and

Suspension)

1. Building 2. Equipment's 3. Purified water 4. Manufacturing

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Part I-D Specific requirements for manufacture of topical products (i.e. External preparations )

1. The entrance to the area where topical products are manufactured should be through a suitable airlock. Outside the airlock, insect outros shall be installed.

2. The air to this manufacturing area shall be filtered through at least 20µ air filters and shall be air-conditioned.

3. The area shall be ventilated. The area shall be fitted with an exhaust system of suitable capacity to effectively remove vapours, fumes, smoke, floating dust particles.

4. The equipment used shall be designed and maintained to prevent the product from being accidentally contaminated with any foreign matter or lubricant.

5. No rags or dusters shall be used in the process of cleaning or drying the process equipment or accessories used.

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Part I-E Specific Requirements For Manufacture Of Metered-Dose-Inhalers

• General • Manufacture of Metered-Dose-Inhalers shall be done under

conditions which shall ensure minimum microbial and particulate contamination.

• Building and Civil Works • The building shall be located on a solid foundation to reduce

risk of cracking walls and floor due to the movement of equipment and machinery. Environmental Conditions

• Where products or clean components are exposed, the area shall be supplied with filtered air of Grade C.

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Part I-f specific requirements of premises, plant and materials for manufacture of active pharmaceutical

ingredients (bulk drugs)

Building and Civil Works Apart from the building requirements contained Part-I, General note, the active pharmaceutical ingredients facilities for manufacture of hazardous reactions, Beta- Lactum antibiotics. Steroids and Steroidal Hormones / Cytotoxic substances shall be provided in confined areas to prevent contamination of the other drugs manufactured. Sterile Products. Sterile active pharmaceutical ingredient filled aseptically shall be treated as formulation from the stage wherever the process demands like crystallization , lyophilisation, filtration etc

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Utilities / Services. Equipment like chilling plant, boiler, heat exchangers, vacuum and gas storage vessels shall be serviced, cleaned, sanitized and maintained at appropriate intervals to prevent mal-functions or contamination that may interfere with safety, identity, strength, quality or purity of the drug product.Equipment Design, Size and Location Equipment used in the manufacture, processing, packing or holding of an active pharmaceutical ingredient shall be of appropriate design, adequate size and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.

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Part- II requirements of plant and equipment

External Preparations Oral liquid Preparation Tablets Powders Capsules Surgical dressing Ophthalmic preparation Repacking of Drugs and Pharmaceutical Chemicals Parenteral preparations Inhalers and vitrallae Parenteral preparations in glass containers

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1)External Preparation

External Preparation :• Mixing and storage tanks (stainless steel)• Jacketed Kettle (steam, gas or electrically heated), Mixer

(electrically operated) • Planetary mixer • A colloid mill or a suitable emulsifier.• A triple roller mill or an ointment mill. • Liquid filling equipment (electrically operated). • Jar or tube filling equipment (electrically operated) Area. - A minimum area of 30 sq. m. for basic installation of ten square meters for Ancillary area is recommended

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2)Oral liquid Preparations• The following equipment's are commended for the manufacture of

oral/internal use preparations namely: - 1. Mixing and storage tanks (stainless steel) 2. Jacketed Kettle / Stainless steel tank (steam, gas or electrically

heated) 3. Portable stirrer (electrically operated) 4. A colloid mill or suitable emulsifier (electrically operated)5. Suitable filtration equipment (electrically operated) 6. Semi-automatic/automatic bottle filling machine 777. Pilfer proof cap sealing machine. 8. Water distillation unit or deioniser 9. Clarity testing inspection units

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3) Tablets

• The tableting section shall be free from dust and floating particles and may be air-conditioned.

• Connected to a vacuum dust collector or an exhaust system.• For effective operations, tablet production department shall be

divided into four distinct and separate sections as follows: -1. Mixing, Granulation and Drying section. 2. Tablet compression section. 3. Packaging section (strip/blister machine wherever required).

Coating section (wherever required).

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The following electrically operated equipment's are recommended for the manufacture of compressed tablets and hypodermic tablets, in each of the above sections, namely: -

a) Granulation-cum-Drying section 1. Disintegrator and sifter 2. Powder mixer 3. Mass mixer/Planetary mixer/Rapid mixer granulator. 4. Granulator 5. Thermostatically controlled hot air oven with trays (preferably mounted on a

trolley)/Fluid bed dryer. 6. Weighing machines. (b) Compression section. 7. Tablet compression machine, single/multi punch/ rotatory . 8. Punch and dies storage cabinets.9. Tablet de-duster 10. Tablet Inspection unit/belt. 11. Dissolution test apparatus 12. In-process testing equipment like single pan electronic balance, hardness tester, friability

and disintegration test apparatus. 13. Air-conditioning and dehumidification arrangement (wherever necessary)

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…..Continue C) Packaging section.1. Strip/blister packaging machine. 2. Leak test apparatus (vacuum system) 3. Tablet counters (wherever applicable) 4. Air-conditioning and dehumidification arrangement (where ever applicable). Area. - A minimum area of sixty square meters for basic installation and twenty square meters for Ancillary area is recommended for un-coated tablets. (d) Coating section5. Jacketted kettle (steam, gas or electrically heated for preparing coating

suspension). 6. Coating pan (stainless steel) 7. Polishing pan (where applicable) 8. Exhaust system (including vacuum dust collector) 9. Air-conditioning and dehumidification arrangement.10. Weighing balance Area. - A minimum additional area of thirty square meters for coating section for basic installation and ten square meters for Ancillary area is recommended

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4) Powders• The following equipment is recommended for the

manufacture of powders,(1) Disintegrator (2) Mixer (electrically operated)(3) Sifter. (4) Stainless steel vessels and scoops of suitable sizes. (5) Filling equipment (electrically operated). (6) Weighing balance. Area. - A minimum area of thirty square meters is recommended

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5)CapsulesCapsules separate enclosed area suitably air-conditioned and dehumidified with an airlock arrangement shall be provided. The following equipment is recommended for filling Hard Gelatin Capsules, namely: - 1. Mixing and blending equipment (electrically or power driven).2. Capsules filling units (preferably semi automatic or automatic

filling machines). 3. Capsules counters 4. Weighing balance.5. Disintegration test apparatus. 6. Capsule polishing equipment.

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6) Surgical DressingSurgical Dressing The following equipment is recommended for the manufacture of Surgical Dressings other than Absorbent Cotton Wool, namely:- 1. Rolling machine 2. Trimming machine3. Cutting equipment.4. Folding and pressing machine for gauze. 5. Mixing tanks for processing medicated dressing. 6. Hot air dry oven. 7. Steam sterilizer or dry heat sterilizer or other suitable equipment. 8. Work tables/benches for different operations Area. - A minimum area of thirty square meters is recommended to allow for the basic installations.

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7) Ophthalmic Preparations.For Ophthalmic Preparations. separate enclosed areas with airlock arrangement shall be provided. The following equipment is recommended for the manufacture under aseptic conditions of Eye-Ointment, Eye-Lotions and other preparations for external use, namely 1. Thermostatically controlled hot air ovens (preferably double ended). 2. Jacketted kettle/stainless steel tanks (steam, gas or electrically heated). 3. Mixing and storage tanks of stainless steel/Planetary mixer. 4. Colloid mill or ointment mill. 5. Tube filling and crimping equipment (semi-automatic or automatic filling. 6. Tube cleaning equipment (air jet type)7. Tube washing and drying equipment, if required Automatic vial washing machine. 8. Vial drying oven. And Rubber bung washing machine. 9. Sintered glass funnel, Seitz filter and filter candle10. Liquid filling equipment (semi-automatic or automatic filling machines). 11. Autoclave ( preferably ventilator autoclave).12. Air conditioning and dehumidification arrangement 13. Laminar airflow units. Area. - A minimum area of twenty-five square meters for basic installation and ten square meters for Ancillary area is recommended

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8) Pessaries and Suppositories

(i) The following equipment is recommended for manufacture of Pessaries and Suppositories, namely: - 1. Mixing and pouring equipment 2. Moulding equipment. 3. Weighing devices. Area. - A minimum area of twenty square meters is recommended to allow for the basic installation. (ii) In the case of Pessaries manufactured by granulation and compression, the requirements as indicated under Item 3 of Tablet, shall be provided.

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9)Inhalers and Vitrallae

The following equipment is recommended for manufacture of inhalers and vitrallae , namely:1. Mixing equipment2. Graduated delivery equipment for measurement

of the medicament during filling.3. Sealing equipment. Area. - An area of minimum 20 square meters is recommended for the basic installations.

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10) . Repacking of Drugs and Pharmaceutical Chemicals

The following equipment is recommended for repacking of drugs and pharmaceuticals chemicals, namely:- 1. Powder disintegrator 2. Powder sifter (electrically operated) 3. Stainless steel scoops and vessels of suitable sizes Weighing and

measuring equipment. 4. Filling equipment (semi-automatic / automatic machines). 5. Electric sealing machine. Area- An area of minimum 30 square meters is recommended for the basic installation. In case of operations involving floating particles of fine powder, a suitable exhaust system shall be provided.

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11)Parenteral Preparations The whole operation of manufacture of parenteral preparations (SVP and

LVP) in glass and plastic containers may be divided. Parenteral preparations in glass containers,- 1. Water management area 2. Containers and closures preparation area 3. Solution preparation area 4. Filling, capping and sealing area 5. Sterilization area 6. Quarantine area 7. Visual inspection area 8. Packaging area Area. - A minimum area of one 150 square meters for the basic installation and an Ancillary area of 100 square meters for SVP are recommended. For LVP an area of 150 square meters each for the basic installation and for Ancillary area is recommended.

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Reference

• Gazette Of India Extraordinary, Part II-section 3, Sub-setion [(I)] Ministry Of Health And Family Welfare(department Of Health) New Delhi, The 11 December, 2001

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