Pharmaceuticals Facility and cGMP Expectations

January 13, 2024October 5, 2016 by Pharmaceutical Guidanace

Current Good Manufacturing Practices in Pharmaceutical Industry

The cGMP requirements are described in the various guidelines which deal mainly in the following categories,

e.g.,

(A) Requirements related to surroundings.

(B) General requirements for pharmaceutical plants.

(D) Requirements related to special products. e.g., sterile products.

(A) Requirements related to surroundings.

“The factory building(s) for manufacture of drugs 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.” Only Indian cGMP guidelines specifically talk about “surroundings” of pharmaceutical plant.

All other international guidelines talk in terms of “General Requirements” and “different plant areas.”

“General Requirements” related to pharmaceutical plants.

(B) General Requirements for Pharmaceutical Plants

1. Pharmaceutical plants must be located, designed, constructed, adapted and maintained to suit the operations to be carried out.

2. Their layouts and design must aim to minimize the risk of errors and permit effective cleaning and maintenance, in order to avoid cross-contamination, built up of dust or dirt and in general any adverse effect on the quality of the product and safety of the personnel.

3. To preventing contamination of drug and addition of extraneous materials to the drug.Regular maintenance of the plants to prevent deterioration of the premises and finally says that the –“Ultimate objective of all endeavours is product quality.”

Pharmaceutical plants must be designed so that they must meet following requirements.

They should be easy to clean, maintain and operate.
Men and materials movement, considering the manufacturing flow charts of the products to be manufactured. Zigzag movements of men and materials should be avoided as far as possible
Avoiding cross contamination and mix-ups.
Layouts include equipment, subsection, section, department etc.
Equipment or workstation is the basic unit of operation e.g., a compression m/c for tablets, a sifter, a capsule filling m/c etc.
For avoiding cross contamination and mix-ups the flow of materials is to be considered as primary aspect and other aspects like, storage of intermediate materials at different stages of processing and packing and also the separation of air handling unit must be considered to avoid contamination of materials.
Manufacturing plants must be situated in such an environment which protect all the manufacturing processes by minimizing the risk of contamination of R.M. /P.M. / Intermediate and finished products.
A careful planning of HVAC system must be done to avoid contamination. Following points must be considered while doing this e.g.,
segregation and clearly defining the scope of individual air handling unit so that only one product is being exposed in that area at any time of operation.
Duct and filter cleaning procedures must be well defined and documented.
The HVAC system details must be worked out very critically, these include details like,
• Temperature
• Humidity
• Differential pressure
• Air changes per hour
• Class of air etc.
Even SOPs related to movement of men from one workstation to other workstation must be clearly defined.
The vacuum cleaning lines laid down in plants with connections at suitable points may be a fast and easy method of cleaning.
The dry dust may be collected by this way at few selected points in the plants, eliminating physical transfer of collected dust from the plant. Suitable trash collection systems may also be planned. Trash collection points may be planned in each section or subsection. Each such trash collection point may have recycled plastic bags put in a suitable wire meshed containers and these bags may be collected along with collected trash at least twice in a shift of 8 hours or whenever required.
Sanitization SOP and records must be in place and followed. Sanitization SOPs should be clearly described for different areas e.g., corridors, engineering service areas, wash places, change rooms, linen rooms, non-sterile processing areas, primary and secondary packaging areas Regulatory and sterile processing areas.
Aseptic operations areas must have vacuum cleaners made up of at least S.S.304 and fitted with additional HEPA filters.
The people doing sanitation work in aseptic areas must be specifically trained in entry and exit from the aseptic area, and method of handling sanitation equipment and other materials like detergents and disinfectants etc for this purpose substances like cresol with soap, (Lysol) which are highly caustic and can result into physical accidents because of its contact to skin or eye etc people must be trained in safety procedures for using such materials and methods of dealing with accidental injuries by such caustic substances. U.S.F.D.A. consider the role of sanitary supervisor as one of the important positions and its detailed job description is demanded by F.D.A. inspectors during their plant audits, hence well experienced and suitably qualified people should be put in charge of this position.
Records of sanitary work carried out as per laid down SOPs must be maintained.

4. Manufacturing plants should always be kept in a good state of repair. It should be so designed, so that the maintenance operations can be carried out without affecting the product quality. Separate service lanes may be provided.

5. SOPs and records should be kept for cleaning, maintenance, disinfection and sanitization.

6. Plants should be maintained in order – • Electric supply • Lighting • Temperature • Humidity • HVAC

A detailed SOP and relevant records should be maintained for building maintenance.
The maintenance activities should cover following areas at the minimum.
(i) Wall and ceiling surfaces. No peel off of paint is permissible; and such situation must be immediately repaired, this is to be considered as one of the main source of material contamination in the processing or other areas.
(ii) Brocken tiles or surfaces can result in accumulation of dust and dirt and also a potential source of physical accidents. Material trolleys can get toppled or material can fall from the trolleys and fall down on the surfaces and needs to be rejected.
(iii) Routine painting of the facility is a must to maintain the facility, always production worthy.
(iv) Plumbing damages, drain chocking, leaking taps and pipe joints must always be immediately repaired and kept in good working conditions.
(v) Electrical wiring and operating switches should be repaired, if found out of order, immediately.
(vi) Doors and windows must always be closed properly. Whenever you have provided interlocking systems, they must always be functioning properly.
(vii) All the lights in all the areas must be working whenever required. Burnt out lamps and tubes must be immediately replaced.
(viii) HVAC systems must always be in working condition and desired levels of environment conditions in terms of temp, humidity, air changes and class of air must be maintained.
(ix) Lawns outside the plants must be hygienically maintained periodic services of a qualified and trained horticulturist may be sought.

7. Plants should be so constructed that they avoid the entry of crawling and flying insects, pests, rodents and other Animals and Birds. A pest and insect control programme should always be in place. Toxic baits should be carefully controlled and used in such a way that they should not present a hazard to product or materials.

Eliminating pests, crawling and flying insects, rodents, birds etc., is a measure problem faced by plant people. It is always advisable to take care of preventive measures during construction of the plant only. e.g.
All doors opening outside must be tight closing so that no space remains open at the side or bottom of closing shutter in closed condition.
Rubber gaskets may be useful at appropriate position, PVC strips, air curtains and insecticutors may Regulatory Requirements for Pharmaceutical Plants be provided.
Warehouses may be provided with spine surfaces at the potential areas where accidently entered birds are likely to sit. Birds can not sit on such surface because they will get hurt.

8. Steps should be taken to prevent the entry of unauthorized people. Particularly no unauthorized person is allowed in the area of production, stores and quality control departments.

Modern pharmaceutical plants should provide small meeting room in the reception or office area, where outside persons can meet the plant people and have discussions; this avoids entering of people who do not need to enter the plant, and still their work can be done. A SOP and record should be in place, where an outsider is required to enter the plant area.

9. Waste materials should be continually removed from the premises and written sanitation procedures available, detailing schedules, methods, materials and equipment. Responsibility should be assigned in writing. Cleaning and disinfection should be on going on a regular basis and must include change rooms, wash rooms toilets and refreshment areas.

A detailed SOP and records for handling and managing waste materials, trash and scrap etc. All such materials coming out from the processing area should be certified before it moves to waste material collection centre.

10. Adequate Lighting:

As per CFR211.44 gives only one line guideline and states that “Adequate lighting shall be provided in all area.” Regulatory guidelines do not make any comment on the intensity of light required in various operational areas. But there are certain industry norms for specific critical areas in the plant they are as follows:

(i) Visual inspection areas for ampoules and vials or similar sterile products – 100foot candle
(ii) Visual inspection areas for liquid oral Bottles or similar non sterile products – 50 to 80 foot candles (iii) Packaging line in packaging department – 50 foot candles
(iv) Visual inspection of tablets/capsules Or automatic, semiautomatic inspection Belts- 50 to 80 foot candles
(v) Other operational areas in plant – 50 foot candle
Such light intensity should be checked at operational height in the department

Regulatory Related To Various Departmental Areas

The regulatory guidelines cover requirements related to the following departments. viz.,

(i) Storage and weighing areas

(ii) Production areas

(iii) Q.C areas

(iv) Sterile – products areas

(v) Ancillary areas covering following

(a) Rest, refreshment rooms and smoking areas.

(b) Change rooms and storing of linen, toilets and washrooms.

(d) Now let us briefly look at the regulatory requirements regarding the above mentioned departmental areas.

Storage and Weighing Areas

• Storage area should be of sufficient capacity to allow orderly storage of the various categories of materials and products; starting and packaging material, intermediates, bulk and finished products, products in quarantine and released, rejected, returned or recalled products.

• Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage condition are required (temp and humidity) there should be provided, checked and monitored.

Storage capacity should be calculated based on following information.
(i) Types of formulation being handled and their volumes per day, week, month etc.
(ii) Inventory to be carried of R.M, P.M and F.G at the plant.
(iii) Specific large volume inventory items to be kept
e.g., (a) Bottles (Glass or plastic) Here the inventory may be required large, depending upon the suppliers production runs.(b) Sugar, where large volumes of syrup based liquid orals are prepared (c) Other formulation based solvents like glycerin, liquid sorbitol, I.P.A, Methylene chloride etc.
(iv) Special products to be stored e.g., sterile drug powders of antibiotics and other of similar substances.
(v) Active and other substances which are required to be stored in special conditions such as • Low temp. (Cool area or cold and refrigerated storage etc.) • Low humidity (vi) Primary packaging materials. (vii) Printed packaging materials.
(viii) Separate suitable and sufficient storage area for returned, recalled, rejected goods etc. Receiving and dispatch bays should protect materials and products from the weather. Reception areas should be designed and equipped to allow containers of incoming materials to be cleaned if necessary before storage.
All receiving and dispatch bays must have an extended weather protection for the goods vehicles standing in front of the receiving or dispatch bay. This protects the materials from rain, storm etc. This can be of permanent nature or it can also be of temporary nature. Temporary shelter protections can be created as and when the goods vehicle arrives at the bay. Such temporary shelters are now available readymade, which are fixed at the opening side of the bay and can be folded or unfolded as per need. Such protections either temporary or permanent should have sufficient length and also have enough protection from other two sides also. This should not be considered only as a legal requirement but should be treated as important requirement during the plant design.
The receiving and dispatch bays should have provisions for vacuum cleaner and may be other suitable cleaning systems. This is required for the cleaning of external surfaces of the containers of materials received at the receiving bay.
The warehouse management should be able to prove that the available cleaning system is able to take care of the cleaning needs. A SOP should be in place and concerned people must be trained. These people should also be able to explain the system to the inspecting authorities.
Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorized personnel. Any system replacing the physical quarantine should give equivalent security.
Identification of materials is one of the major cGMP requirements.
The R.M /P.M received may go on changing its identity without having any change in its physical appearance. e.g. A material received may have following changes in identity like – Material received – Material sampled – Material under test – Material approved – Material rejected etc.
The ware house should be provided with specific areas either by permanent segregation or by temporary segregation for the above categories of materials and no unauthorized person should be allowed to make any change in this situation.
There should normally be a separate sampling area for starting materials (e.g., raw and packaging materials) If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross contamination.
Warehouse should be provided with separate areas for sampling and dispensing of following categories of materials.
(i) Active non sterile substances (general category)
(ii) Active non sterile substances (β- lactam and other specific / sensitive materials.)
(iii) In active raw materials.
(iv) Liquids and semisolid materials either active or inactive.
(v) Sterile powder substances. **
(vi) Highly toxic, poisonous or hazardous materials.
(vii) Primary packaging materials.
A SOP clearly defining the area and sampling and dispensing procedure must be in place and records of such activities carried out should be made in chronological fashion in a log book. (This should include Date and Time also.)
** Normally sampling of sterile powder e.g., antibiotics are carried out in either Q.C labs or in production areas. This always have problem regarding time slots being made available for sampling.
• Segregation should be provided for the storage of rejected, recalled, and returned materials or products.
Depending upon the volumes expected to be handled and the material is likely to stay in ware house following areas should be planned in a segregated fashion.
e.g., • Rejected materials • Returned materials • Recalled materials • Highly active material, narcotics, other dangerous drugs, and substances presenting special risks of abuse, fire or explosion should be stored in safe and secure areas.
Expected formulations to be made in the plant should be carefully studied for the materials to be used and their volumes required to be handled and stored, in the following categories namely: (i) Highly active materials (ii) Narcotics (iii) Dangerous drugs/ Technical poisons like pesticides and herbicides (iv) Explosive materials (v) Poisons (e.g., pot. cyanide etc.) Suitably secured areas of suitable sizes at appropriate places should be provided in the design of stores and ware houses.
Printed Packaging Materials are considered critical to the conformity of the pharmaceutical product to its labeling and special attention should be paid to the safe and secure storage of these materials.
Storage of printed packaging materials must be segregated and have the rooms lockable, along with the storage cupboards also lockable. The main problem comes for the storage of carton which are printed and requires relatively large volumes for storage as compared to the labels, which are generally stored in the pigeon hole cupboards.
Lockable big areas may be also provided with wire mesh segregation can be thought of for storage of printed cartons. Printed and unprinted foils can be stored on solid rods slightly inclined upwards to avoid damage of sides of the rolled foils.
Relatively clean areas ( class 10000) may be provided for sampling of primary packaging materials. (M.H.R.A. inspector had asked for such a facility in one of the audit, which the author has faced in the year 2004.)
• Storage areas should be clean and dry and maintain acceptable temperature and humidity limits. • Specials storage areas such as cold rooms or low humidity rooms should be provided for materials that require these conditions.
The environment should be continuously monitored and equipped with alarms to alert personnel in case of failures, so that alternative arrangements can be made.
Volumes handled and normal period of storage should be considered while providing the storage area for materials required to be stored at low temp. and low humidity.
• Warehouses that are not computer controlled should provide separate areas clearly demarcated and preferably physically separated for following categories of materials – sampling, quarantine, raw, packaging intermediate, finished products, rejected, recalled and returned materials or products. Areas must be restricted to authorized personnel only.
• Computer controlled warehouses must have a system which gives equivalent security.
Warehouses should be provided with sufficient spaces for office work, computer room etc. Depending upon the activity following areas should be considered.
(i) Cabin for warehouse manager and other senior people who will be sitting in this area.
(ii) Office for ware house (one or more)
(iii) Office record rooms / Stationary storage
(iv) Computer room. etc.
• Warehouses should be secured against theft and the important medicines and raw materials should be locked in separate secured areas.
Weighing Areas
The weighing of starting materials and the estimation of yields by weighing should be usually carried out in separate weighing areas designed for that use, e.g., with provision for dust control.
Production Areas
In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials. e.g., (penicillin) or biological preparations (e.g., live micro organisms) the production of certain other products such as some antibiotics, hormones, cyto toxic substances, highly active pharmaceutical products should not be conducted in the same facilities.
Formulation wise production areas are any way separate in the same building but if we plan to handle sensitive products, the areas should be preferably in separate buildings which are sufficiently apart and the normal wind direction should be from non sensitive to sensitive products facilities.
1.The HVAC and water system should be separate.
2. The people working in these areas must not have free access to other areas.
3. Uniforms used by people in sensitive product areas must be laundered separately, preferably after decontaminating (or desensitizing).
4. The exhausted air from sensitive product area should be first decontaminated / desensitized by suitable scrubbing method (e.g., pH 8 solution of NaOH for β-Lactum etc). A provision for air sampling after scrubbing should be available to confirm no sensitive material is passed in the atmosphere.
5. Except senior supervisory staff all people working in the area should be separate.
Facilities for restroom, snacks and dining should also be separate. The main idea behind this is, all possible care should be taken to avoid cross contamination.
• The manufacture of technical poisons, such as pesticides and herbicides should not normally be allowed in premises used for manufacture of pharmaceutical products.
In exceptional cases, the principle of campaign working in some facilities can be accepted provided that specific precautions are taken and the necessary validations are made.
Campaign working is accepted only in exceptional cases. In such cases following points should be kept in mind.
(i) SOP and records for decontamination and sanitization should be in place and followed.
(ii) Cleaning, sanitization and decontamination procedures must be fully validated.
This should be considered for both, facilities and equipment used. In short, everything which comes in contact with such materials like technical poisons such as pesticides and herbicides must be decontaminated before the manufacture of other products start in the same area. Such procedures carried out must be put on record.
• Premises should preferably laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to sequence of the operations and to the requisite cleanliness levels.
While designing the production areas flow diagrams of material movement as per the progression of the process and also the men movement should be considered to avoid zigzag movement of materials and men both. Such designed facilities should be easy to operate clean and maintain.
• The adequacy of working and in process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components to avoid cross contamination and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.
Pharmaceutical plant designers should consider following points.
(i) All equipment placed in the plant should be such that it can be easily and conveniently approachable for operation, cleaning and maintenance.
(ii) A service passage may be provided from behind the equipment wherever possible, processing part of the equipment and electro mechanical part of the equipment may be separated by S.S. partition. This may be possible in case of big blenders; F.B.Ds etc.
(iii) The flow diagram should show where the in-process materials are required to be stored. Depending upon the volumes of such materials and normal time of the storage area should be planned. Neglecting these things during planning may result in accumulation of materials in processing area, resulting in danger of cross contamination and mix-ups.
• Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces, (walls, floors and ceilings) should be smooth and free from cracks and open joints should not shed particulate matters and should permit easy and effective cleaning and if necessary disinfection.
• Pipe work, light fittings, ventilation points and other services should be designed and fixed to avoid the creation of recesses that are difficult to clean. As far as possible, for maintenance purpose, they should be accessible from outside the manufacturing areas.
Service pipe lines like, different types of waters (Raw, Potable , Purified, Soft, W.F.I) steams ( plant steam and purified steam) other gases etc should preferably be drawn from outside the processing area, if possible from top or service ceiling floor and dropped down at the points of use through closed, seamless, S.S. conduits. All such lines must be marked with direction of low and contents inside. International guidelines may be needed for identifying the contents for different gases and other solvents etc. since every one working in the area may not be fully aware of such markings hence plain word-writing is still preferable.
• Drains should be of adequate size and equipped to prevent backflow. Open channels should be avoided where possible, but if they are necessary they should be shallow to facilitate cleaning and disinfection. If drains are connected directly to a sewer, shall be provided with an air break or other mechanical device to prevent back-siphorage.
Open channels, even though shallow, may still be covered with light wet, easily removable and cleanable, preferably transparent cover of suitable size. • Potable water shall be supplied under conditions of positive pressure in a plumbing system free of defects that could contribute contamination to any drug product. Potable water shall meet the standards prescribed in the Environmental Protection Agency’s Primary Drinking Water Regulations set forth in 40CFR part 141or any relevant country’s requirements. Water not meeting such standards shall not be permitted in potable water system.
Additionally advantages may be taken of chilled water lines available for cooling the potable water if so desired.
• Production areas should be effectively ventilated, with air-control facilities (e.g., temp, humidity, filtration etc.) appropriate to products handled, to the operations under taken, and to the external environment. These areas should be regularly monitored during production and non-production periods to ensure compliance with their design specification.
These days, normally the HVAC system is installed above the ceiling of the processing area, and ducts of supply are dropped from the top and returns are taken from bottom of the room through closed systems embedded within the room walls.
Scope of each HVAC system and U.R.S requirements must be clearly discussed before the finalization of the HVAC system for each processing area.
The HVAC URS should consider at least following points in this regard.
(a) Types of products to be handled in the area.
(b) No. of people working in the area.
(c) Heat generated by equipment in operation.
(d) Temp and humidity requirements.
(e) No. of air changes per hour.
(f) Differential pressure desired.
(g) Class of air required to be maintained as per cGMP requirement (e.g., class 100, 10000, 100000 etc.)
• In case where dust is generated (e.g., during sampling, weighing, mixing and processing operations, packaging of dry products) specific provisions should be made to avoid cross-contamination and facilitate cleaning.
Separate, effective dust collection systems must be provided, plant design should consider these points. So that appropriate openings in ceiling or in walls may be provided during construction of the plant itself.
• Equipment for adequate control over air pressure, microorganisms, dust, humidity and temperature shall be provided when appropriate for manufacture, processing, packing or holding of a drug product.
• Air filtration systems, including pre filters and high efficiency particulate matter air filters, shall be used when appropriate or airsupplies to production areas. If the air is re circulated to production areas, measures shall be taken to control re- circulation of dust from production.
In areas where air contamination occurs during production, there shall be adequate exhaust systems or other systems adequate to control contaminants.
• Air handling systems for the manufacture, processing and packing of penicillin (and other β-Lactam products) shall be completely separate from those for other drug products for human use.
• Premises for packaging of pharmaceutical products should be specifically designed and laid out so as to avoid mix-ups or cross contamination.
Normally primary packaging and secondary packing must be separated. Following areas may be considered in this as primary packaging.
(a) Strip sealing and blister packaging of tablets and capsules.
(b) Dry syrup filling
(c) Liquid oral bottle filling
(d) Ointment / Cream tube filling and sealing etc.
(e) Granule Filling area
• In-process controls may be carried out within the production areas provided they do not carry any risk for the production.
All production department should have a separate IPQA, following areas may be considered.
(i) Tablet compression area.
(ii) Capsule filling area.
(iii) Strip sealing and blister packing area.
(iv) Liquid filling area.
(v) Soft Gelatine Area
(vi) A non-sterile room in injection department for IPQA of filled ampoules/vials.
• Production areas should be well lit, particularly where visual online controls are carried out.
Quality Control Areas• Quality control laboratories should be separated from production areas. Areas where biological, micro-biological tests are employed should be separated from each other.
• Control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mixups and cross contamination. There should be adequate suitable storage space for samples, reference standards (if necessary, with cooling) and records.
• The design of the laboratories should take into account the suitability of construction materials, prevention of fumes, and ventilation. Separate air-handling units and other provisions are needed for biological, micro-biological and radioisotope laboratories.
• A separate room may be needed for instruments to protect them against electrical interference, vibrations, contact with excessive moisture and other external factors or where it is necessary to isolate the instruments.
In addition to the point written above designing of the quality control labs should consider following area • Office for QC staff • Library and conference room • Stores for glassware, chemicals, microbial media, stationary etc. • Control samples room. • Records room. • Strong room for storage of government original documents like various licenses etc. • Change rooms for QC staff with wash facility.
Sterile Products Area
Sterile-products manufacturing areas should give attention to following points:
• All premises should as far as possible designed to avoid the unnecessary entry of supervisory or control personnel.
Grade “B” areas should be designed so that all operations can be observed from outside.
• In clean areas all exposed surfaces should be smooth, impervious and unbroken in order to minimize the shedding or accumulation of particles or micro-organisms and to permit the repeated application of cleaning agents and disinfectants used.
• To reduce the accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboard and equipment.
Doors should be carefully designed to avoid uncleanable recesses; sliding doors are undesirable for this reason.
• False ceilings should be sealed to prevent contamination from space above them.
• Pipes and ducts should be installed so that they do not create recesses that are difficult to clean.
• Sinks and drains should be avoided where ever possible and should be excluded from areas where aseptic operations are carried out. Where installed they should be designed, located and maintained so as to minimize the risk of microbial contamination, they should be fitted with effective, easily cleanable traps with air break to prevent back flow. Any floor channel should be open and easily cleanable and be connected to drains outside the area in a manner that prevents ingress of microbial contamination.
• Changing rooms should be designed as airlocks and used to provide separation of the different stages of changing, so minimizing microbial and particulate contamination of protective clothing. They should be effectively flushed with filtered air. The use of separate changing rooms, for entering and leaving clean areas is sometimes desirable.
• Hand washing facilities should be provided only in the first stage of changing rooms, not in areas where aseptic work is done. The final stage of the changing room should in the at rest state, be the same grade as the area into which it leads.
• Air lock doors should not be opened simultaneously. An interlocking system and a visual and / or audible warning system should be operated to prevent the opening of more than one door at time.
• A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively.
Adjacent room of different grades should have a pressure differential of 10-15 pascals (General Guidelines) particular attention should be paid to the protection of the zone of greatest risk, that is, the immediate environment to which the product are exposed clean components which contact the product are exposed.
Decontamination of facilities and treatment of air leaving a clean area may be necessary for some operations.
• It should be demonstrated that air flow patterns do not present a contamination risk e.g., care should be taken to ensure that air flows do not distribute particles from a particle generating person, operations or machine to a zone of higher product risk.
• A warning system should be provided to indicate failure in the air supply. Indicators of pressure differences should be fitted between areas where these differences are important. These pressure differences should be recorded regularly or otherwise documented.
• In addition to above points discussed from various regulatory guide lines following points must also be considered. These are discussed in “Annex-1” of orange guide under the title of “Manufacturing of sterile medicinal products.”
• The manufacturer of sterile products should be carried out in clean areas, entry to which should be through air locks for personnel and / or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency.
• The various operations of component preparation product preparation and filling should be carried out in separate areas within the clean area. Manufacturing operations are divided into two categories, firstly those where the product is terminally sterilized, and secondly those which are conducted aseptically at some or all stages.
• Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimize the risk of particulate or microbial contamination of the product or material being handled.
In order to meet “In Operation” conditions these areas should be designed to reach certain specified air cleanliness levels in the “at rest” occupancy state.
The “at rest” state is the condition where the installation is complete with production equipment installed and operating but with no operating personnel present.
The “In Operation” state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working.
For the manufacture of sterile products normally 4 grades can be distinguished.
Grade A: The local zone of high risk operations e.g., filling zone, stopper bowls, open ampoules and vials making aseptic connections. Normally such conditions are provided by a laminar-air-flow work station. Laminar air flow systems should provide a homogeneous air speed of 0.45 met/sec. ±20% (i.e. 72 to 108 feet /min) (Guidance Value) at the working position.
Grade B: In case of aseptic preparation and filling the background environment for grade A zone.
Grade C and D: Clean area for carrying out less critical stages in manufacturing of sterile products. The airborne particulate classification for these grades is given in the following table.
Grade At Rest (b) In Operation(c) Maximum permitted number of particles /m3 0.5µm 5 µm 0.5 µm 5 µm A 3500 0 3500 0 B (a) 3500 0 350000 2000 C (a) 350000 2000 3500000 20000 D (a) 3500000 20000 Not defined Not defined
In order to reach B, C and D air grades, the number of air changes should be related to the size of the room and the equipment and personnel present in the room.
The air system should be provided with appropriate filters such as HEPA for grade A, B and C.
The guidance given for maximum permitted number of particles in the “at rest” condition corresponds approximately to US federal standard. 209E and the ISO classifications as follows:
Grades A and B – Corresponds to class 100, M3.5, ISO5
Grade C – Corresponds to class 10000, M5.5, ISO7
Grade D – Corresponds to class 100000, M6.5, ISO8
The requirement and limit for this area will depend on the nature of the operations carried out.
Examples of operations to be carried out in the various grades are given in the table below. Grade Examples of operations for terminally sterilized products A Filling of products, when unusually at risk.
C Preparation of solutions, when unusually at risk filling of products
D Preparations of solutions and components for subsequence filling Grade Examples of operations for aseptic preparations
A Aseptic preparation and filling C Preparations of solutions to be filled D Handling of components after washing The particulate conditions given in the table for the “at rest” state should be achieved in unmanned state after a short “clean-up” period of 15 to 20 minutes, (Guidance value) after completion of operation.
The particulate conditions for Grade A in operation given in the table should be maintained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment. It is accepted that it may not always possible to demonstrate conformity with particular std. of the point of fill when filling is in progress, due to generation of particle or droplets from the product itself.
• In order to control the particulate cleanliness of the various grades in operation, the areas should be monitored.
• In order to control the microbiological cleanliness of the various grades in operations the areas should be monitored.
When aseptic operation is performed monitoring should be frequent using methods such as settle plates, volumetric air and surface sampling. (e.g., swab or contact plates) Sampling methods used in operation should not interfere with zone protection.
Results from monitoring should be considered when reviewing batch documentation for finished product release. Surfaces and personnel should be monitored after critical operations.
Additional microbiological monitoring is also required outside production operations e.g., after validation of systems, cleaning and sanitation. Recommended limits for microbiological monitoring of clean areas in operation.

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