FACILITY VALIDATION

1.0 Purpose:

The purpose of this document is to qualify new facility, in order to establish documented evidence that the facility has been designed and installed as per the approved design specifications, made operational, perform as intended and meets the requirements of national and international requirements/ guidelines for c GMP`s, safety and environment.

2.0 Reason for Establishing protocol for qualification of the facility:

Facility has been designed and constructed to facilitate manufacturing and packing of tablets, hard gelatin capsule and dry syrups formulations at Bommasandra Industrial area. Hence qualification of the facility is planned.

3.0 PROTOCOL APPROVAL SIGNATURES

4.0 Scope:

This protocol is applicable for qualification of the facility of Micro labs limited, Bommasandra, Bangalore.

5.0 Validation team and responsibilities:

Engineering Department: Execution, compilation and review of data

Quality Assurance : Preparation, review and approval of the protocol

Production : Checks and Review

Quality control : Execution of the protocol.

6.0 Design Qualification (DQ):

6.1 Purpose:

The Purpose of design qualification is to ensure that all the critical aspects of cGMP’s, Product/Process requirements, safety, environment, ergonomics, statutory requirements and environment

controls have been considered in designing the new facility and the same has been complied & documented

6.2 Facility Design in brief:

Ground floor: Raw material store, Packing material store, tablet manufacturing area, capsule manufacturing area, dry syrup manufacturing area, primary packing cubicle, bulk storage area, secondary packing area, Finished goods store, washrooms, change rooms (Primary and secondary), cleaned equipment storage area, Dispensing area, purified water plant.

First floor : Quality control laboratory, Quality assurance

Service floor: Air handling systems/ utilities

7.0 Critical Attributes to be met while designing the facility:

7.1 Layout and Design must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross contamination, build up of dust or dirt and in general any adverse effect on the quality of products.

7.2 Location and surroundings:

All Measures to be considered in order to avoid risk of contamination from external environment which includes open sewage, drain, public lavatory or any factory which produces disagreeable or obnoxious odor, fumes, excessive soot, dust, smoke or chemical emissions.

7.3 Premises:

Premises shall be designed & equipped so as to afford maximum protection against the entry of rodents, crawling insects, flying insects, lizards, flies, birds & other animals.

7.3.1 The premises shall be provided with adequate working space to allow orderly & logical placement of equipments.

7.3.2 Movement of materials and personnel shall be considered while designing the facility so as to avoid any risk of mix-up, avoid possibilities of contamination, cross contamination & crisscross movements.

7.3.3 Lighting shall be given due importance in all areas within & outside the facility so as to carryout various operations with ease & comfort. Emergency lights shall be provided in corridors, process areas, Stores, packaging areas and stairs.

7.3.4 Drain pits shall be designed to prevent back flow, wherever drainage is provided, the same shall be concealed.

7.3.5 Air handling systems shall be designated to provide class 100,000 at rest in areas where product is directly exposed to environment. Air handling systems shall be dedicated to avoid possibilities of cross contamination.

7.3.6 Wood shall not be used anywhere in the production and storing area.

7.3.7 Anti-Termite treatment shall be carried out below the floor bed, flagging concrete around the building and walls within the facility.

7.3.8 Adequate areas shall be designated to allow sufficient and orderly warehousing of various categories of materials and products like starting ( raw materials ) and packing materials, intermediates, bulk and finished products, products in quarantine, released, rejected, returned or recalled.

7.3.9 Temperature & related humidity controls shall be provided for storage of empty & filled capsules. Areas for processing of capsule formulations shall also be temperature & relative humidity controlled.

7.3.10 Receiving & despatch bays shall protect materials & products from adverse weather conditions.

7.3.11 Various areas in the stores shall be clearly segregated. Any system replacing physical quarantine shall give equivalent assurance of segregation.

7.3.12 There shall be separate sampling area in the Stores with class 100,000 environment reverse LAF.

7.3.13 Segregation shall be provided for storage of rejected, recalled or returned materials or products.

7.3.14 Separate, safe & secured area shall be provided for printed packaging materials.

7.3.15 Dispensing area(s) with class 100,000 environment & reverse LAF shall be provided.

7.3.16 Production areas shall be designed to allow the production in uni-flow with logical sequence of operations.

7.3.17 Working & in process space shall be adequate to permit orderly & logical positioning of equipments & man-material movements.

7.3.18 Electrical fittings, pipe work, ventilation openings & service lines shall be designed, fixed and constructed to avoid creation of recesses. They shall be concealed. Service lines shall be identified by colors & the nature of supply & the direction of flow shall be marked/indicated.

7.3.19 Primary & secondary change rooms for gowning/degowning shall be provided.

7.3.20 Toilets shall be separate for males & females. Toilets shall not be directly connected with production or storage areas.

7.3.21 Quality control laboratory shall be independent from the production areas. Separate areas shall be provided each for physico-chemical, microbiological, instruments and packing materials testing.

7.3.22 Modular furniture shall be provided in Quality Control laboratory.

7.3.23 Sufficient & suitable storage space shall be provided for test samples, retained samples, reference standards, records etc.

7.3.24 Separate AHU shall be provided for microbiological laboratory.

7.3.25 Laboratory shall be provided with potable water & purified water for cleaning and analysis purposes.

7.3.26 Microbiological section shall have arrangements such as air locks & laminar airflow workstation.

7.3.27 Packaging lines shall be independent & adequately segregated.

7.3.28 Lighting in each area of the facility shall be adequate enough to perform activities with ease and comfort.

7.3.29 Lighting fixtures shall be of clean room type.

7.3.30 Dust extraction system to be considered in process area where generation of powder dust is expected during processing.

7.4 Floor:

7.4.1 The floor shall be hard, smooth, non-porous, washable, continuous, chip resistant and durable. There shall be no crevices, cracks or open joints in the floor, epoxy floor shall be considered in areas where product is exposed .

7.4.2 Floor to wall joint shall be coved.

7.4.3 Material used for flooring shall permit easy cleaning and shall not shred any particulate matter.

7.4.4 Vitrified tiles shall be used in toilets, in quality control laboratory and in Quality assurance.

7.5 Walls:

7.5.1 The external walls shall be cement plastered, made with table-molded bricks .

7.5.2 The internal partition walls shall be made with cement concrete blocks, cement plastered and painted to smooth finish, anti-static, anti-fungal and avoid flaking.

7.5.3 Internal walls shall be non-porous, smooth and washable. Corners shall be rounded, no crevices or recesses or protrusions or joints, chip resistant and minimum seams.

7.6 Ceiling:

7.6.1 The ceiling shall be hard, non porous, smooth, cleanable and chip resistant.

7.6.2 False ceiling wherever considered shall be made up of Gypsum Board, painted with polyurethane paint / Emulsion paint.

7.6.3 The wall to ceiling joints shall be coved.

7.7 Paint:

7.7.1 Polyurethane / Emulsion paint over the primer.

7.8 Doors and View panels:

7.8.1 The doors shall be non-porous, smooth, cleanable and flushed with its view panel.

7.8.2 The doors shall be polyurethane coated.

7.8.3 Double glass sealed view panels.

7.8.4 Doors shall open on the same side of the airflow.

7.9 Utilities to be provided:

7.9.1 Air handling units ( Re-circulatory, once through and ventilation).

7.9.2 Purified water system with distribution network in the form of loop.

7.9.3 Compressed air system with distribution network.

7.9.4 Steam

7.9.5 Chilled water

7.9.6 Effluent treatment plant

7.9.7 Power generator backup

7.9.8 Dust extractors in areas where powder dust is generated.

7.10 Electrical requirements:

7.10.1 Single phase & three phase electrical points shall be provided in the facility as per design requirements.

7.10.2 Critical areas and critical equipments shall have back up system in the event of power failure.

7.10.3 Earthling shall be provided to all the points.

7.10.4 Electric wiring shall be concealed.

Flame proof wherever required to be provided.

7.10.5 The lighting units are scientifically apportioned so as to provide adequate light

for the area in which they are used.

7.10.6 Light fixtures shall be accessible to allow proper maintenance, cleaning & to prevent accumulation of dust or foreign matter.

7.11 Safety aspects:

7.11.1 Emergency exits

7.11.2 Smoke detectors

7.11.3 Fire extinguishers.

7.11.4 Easy access to first aid kit.

7.11.5 Camera system.

7.11.6 Solvent storage complying the local statutory regulations.

7.11.7 Round the clock security for the premises

7.12 Regulatory Requirements

(Necessary approvals shall be obtained from following government agencies)

7.12.1 Industrial development corporation, Karnataka.

7.12.2 State electricity board

7.12.3 State pollution control board

7.12.4 Factory inspectorate.

7.12.5 Food and drugs administration, Karnataka.

7.13 Equipments:

7.13.1 cGMP complied process equipments are provided to prevent cross contamination.

7.13.2 Automated material handling systems to minimize manual handling. 8.0 Design specification: (Room/Section wise):

Design specifications in minute details shall be finalized for each room/section of the Facility .Design Requirements with respect to following points shall be finalized & enclosed to this protocol

8.1 Room Dimensions (L x B x H).

8.2 Area in Sq. feet.

8.3 Floor.

8.4 Coving.

8.5 Walls.

8.6 Doors.

8.7 Door closure.

8.8 Vision panels.

8.9 Ceiling/ False ceiling.

8.10 Paint.

8.11 Electrical fittings, lighting fixtures.

8.12 Drainage.

8.13 Utilities Points.

8.14 Air inlet/ Return grills

8.15 Machine

8.16 Temperature

8.17 Humidity

8.18 Pressure differential

8.19 HVAC

8.20 Water system

8.21 Area Qualification ( AQ):

a) Pressure differential

b) Non- Viable particle count

c) Temperature mapping of raw material store

d) Temperature monitoring.

8.21.1 Microbial monitoring:

a) Settle plate count

b) Volumetric air sampling for viable count.

c) Swab test

d) Rinse analysis

e) Drainage swabs

9.0 Installation Qualification:

9.1 Purpose: Purpose of installation qualification is to establish documented evidence that the facility has been designed and constructed as intended and deviations, if any are justified & recorded.

9.2 Facility Layout (To Scale)

Approved layout of each floor (Ground floor, First floor and Service floor) shall be matched with the actual floor construction. Any deviation to the approved layout shall be documented, Justified and approved by corporate technical team & project head. Impact of the same shall be assessed with respect to product quality.

9.2 Facility within and outside shall be assessed with respect to compliance of cGMP’s related to location, surroundings and premises.

9.3 Room data sheets: Refer design requirements of each room/ area/section. Verify the compliance & record. Any deviation shall be documented, discussed & approved incase it is concluded that the deviation shall have no impact directly or indirectly on the product quality. If otherwise, required actions shall be taken & documented.

9.4 Termite treatment certificate, FDA license to manufacture drug products in the new facility, approved layouts (Floor wise), certificates from various contractors (civil, electrical) and from various government agencies shall be attached to installation qualification report.

9.5 Changes made in the facility layouts since the start of construction of the facility shall be documented, giving justification for each change made in the layout or design specifications.

9.6 Acceptance Criteria:

The facility shall meet approved design requirements and floor layouts. Any change in the approved design or layout shall be through change control and documented. Deviations if any shall be justified, assessed, approved and documented.

10.0 Operational qualification:

Every room/ section on each floor shall be checked for flawless and smooth functioning of the following as applicable. Any discrepancy shall be identified, corrected and documented.

10.1 Opening of the doors.

10.2 Closing of the doors.

10.3 Door locks (Lock & Unlock)

10.4 Door handles & hinges

10.5 Door closure.

10.6 Light source & fixtures.

10.7 Electric points & their earthling.

10.8 Water points.

10.9 Compressed air use points.

10.10 Air Handling Unit.

10.11 Differential pressure.

10.12 Drain Points.

10.13 Acceptance Criteria:

Intended out put of the above features shall be met for each room/section as applicable.

11.0 PERFORMANCE QUALIFICATION:

Performance Qualification of various support services provided in each room are detailed in the respective utility protocols

12.0 Requalification criteria:

12.1 Any change/ modification is made in the facility design or layout. The affected area shall be requalified and the room data sheet of the affected area shall be updated to incorporate the change(s) made.

12.2 Any change made in the existing area support services or new or additional features are added to the room.

13.0 Discussions & Summary:

Data collected during the execution of this protocol shall be compiled and evaluated and discussed. Summary report shall be prepared.

14.0 Conclusions and final approvals:

From the data compiled, a summary report shall be prepared. Corporate technical team shall review and approve the final summary report prior to handling of the building for regular use.

15.0 Attachments:

Approved drawings

Door specifications

Certificates

Total Material Control: DAI Software extends material tracking effectiveness

Pharmaceutical operations are subject to same commercial pressures as R&D, production and distribution operations in other industries, but with a critical difference. The strong regulatory framework under which the Pharmaceutical and the related Nutrition industry operates means that issues of material tracking and batch traceability, which for some are the icing on the cake, are absolutely at the heart of the business. Requirements such as these put additional demands on the materials handling and warehousing systems that are used.

Many material tracking functions are managed through modules within high lever corporate systems (eg ERP), which cannot fully support the demanding operations in warehouses, R&D and production. This is especially true in time critical or high throughput environments with both manual and automated materials handling technology or in situations where material tracking must cross organisational boundaries. Under these circumstances, the choice is either to:

• implement a separate, stand alone Material Tracking System, with all the required functionality - usually a major, time consuming and expensive task, or
  
• put in a "Front End" application to extend the capabilities of the existing systems and overcome their limitations - often a much simpler and lower cost option.

Digital Applications International (DAI) has developed "Total Material Control" (TMC), a system that provides these "Front-End" capabilities. TMC boosts material tracking performance in by providing accurate, real-time, supervisory control of all movement activities. John Millard, TMC Product Manager at DAI stated, "Integrating TMC with an existing high level system will deliver financial benefits in R&D, production and warehouse and distribution operations. Typical savings following a TMC installation include reduced labour costs due to increases in staff effectiveness and efficiency, reduced rework by achieving near 100% picking and stock level accuracy and reduced inventory and write off costs through better stock visibility and accuracy."

TMC works in fully automated, fully manual and mixed movement environments. It makes use of barcoding and radio data terminal technology to control material movements not only between operations at a given location but also between locations. TMC controls all physical material movements. TMC issues instructions to operatives, who confirm completion of their operations using fixed, portable or vehicle mounted terminals. TMC also sends instructions to materials handling equipment such as cranes, conveyors, sortation equipment and Automatic Guided Vehicles via equipment controllers, and receives status information in return.

Describing TMC's movement control functionality, DAI's Millard continued "Once the higher level system has issued a Transport Order, TMC takes responsibility for executing it at the correct time, making the most efficient use of the available resources. TMC uses its knowledge of the routes between the required start and end point, together with their current status to subdivide the order into a set of low level movement instructions that are given to the appropriate device for execution. TMC keeps track of the position and status of every unit of material - pallet, container or even item - while in transit and when at its final destination."

With the Pharmaceutical market in mind, where cGMP compliance is mandatory, the TMC family of products has been developed within DAI's proven quality assurance framework specifically aimed at systems requiring pharmaceutical validation. This provides the documented evidence that the underlying design has the integrity needed to ensure that the system will repeatedly and reliably do what it purports to do. DAI's TMC is now in operational use in pharmaceutical production units and distribution warehouses in the UK, mainland Europe and the USA.

Source: Digital Applications International

All About Pharmaceutical Validation and Storage

The pharmaceutical process development is designed to cover a wide array of procedures designed to ensure an efficient business environment. In order to reach the highest level of efficiency, many of today’s pharmaceutical companies seek to outsource their services to companies that specialize in offering various pharmaceutical services. Such companies are used either as providers of, or validation for, sample storage and pharmaceutical storage, drug shelf life validation, stability test, humidity chamber validation or storage, environmental test chambers, and much more. The pharmaceutical validation services provided, are designed make sure that the equipment used by pharmaceutical and biotechnology specialized companies, is in line to meet the current strict environmental conditions.

Pharmaceutical validation companies, such as Pharmaceutical Stability, provide cost effective turn key effective solutions to their clients’ validation and compliance challenges. This US company has excellent track records in providing emergency responses to critical compliance situations that their clients encounter, as well as with setting up qualification and validation programs.

The list of services being offered by such companies include, but are not limited to, project management, design qualification, start-up and commissioning, protocol execution, final report development, customized validation master plan development, protocol execution, performance qualification, and many more. Aside from services such as pharmaceutical storage, pharmaceutical validation, and other direct services, the list of services provided by Pharmaceutical Stability are meant to ensure their customers achieve maximum productivity through discovering any potential problems and errors in the process development.

In terms of pharmaceutical validation services, Pharmaceutical Stability provides comprehensible and exhaustive directions and instructions meant to be easy to implement. When pharmaceutical companies use correct strategies for every section of its activities such as research, product development, and operational management, they maximize their profits and operations. For example, long term and short term validated stability storage services for pharmaceutical products and biotechnology products are now being offered by numerous outsourcing companies. Pharmaceutical Stability provides professional pharmaceutical storage environments that are Q1A compliant and meet all the ICH strict operational guidelines.

Specialized companies which offer pharmaceutical validation, pharmaceutical storage, and drug shelf life validation services, are using the latest in pharma storage equipment. They are able to help client companies improve numerous aspects of their business from product development, drug shelf life, and even production capacity, plus overall productivity. By employing the services of such pharmaceutical validation companies, client companies are able to profit from state-of-the-art technology without having to make any of the large investments that are normally needed to access such services. The process development testing services cover a range of numerous services including pharmaceutical validation services, process mapping, product and operational analysis,

The US Food and Drug Administration’s Draft Guidance for Industry

—Process Validation: General Principles and Practices provides a life-cycle approach for validating pharmaceutical processes and aims to help pharmaceutical companies achieve consistently high product quality. The document includes several concepts that are familiar to the industry but also contains ambiguities and recommendations that might be difficult for some drugmakers to follow.
The draft guidance suggests manufacturers establish links from their clinical process to their commercial-manufacturing process. This approach is similar to the one FDA has used in its preapproval inspections. If the guidance becomes final as it currently stands, manufacturers may be expected to use the data that they gain during formulation and development to define a product’s critical attributes, which would be the basis for the manufacturing-process parameters.
The agency points out that development and formulation data can improve a company’s understanding of its processes during scale-up and commercial manufacturing. This understanding would help companies control variability and increase product quality, says Chris Ames, director of global validation at Catalent Pharma Solutions (Somerset, NJ). Companies would submit these data to FDA to establish links between clinical and commercial processes.
But the draft guidance does not advise manufacturers about how to identify the most important characteristics of its product or manufacturing process, or about how to demonstrate links from the clinical to commercial process. “They’ve left it completely open to interpretation as to what data you provide and what format you use,” says Jim Agalloco, president of Agalloco and Associates. This ambiguity would suit Big Pharma because it frees companies to use their experience and discretion in deciding how to follow the guidance, says Agalloco. Small and emerging drugmakers, however, would likely be confused because they don’t have the depth of knowledge that would help them define critical attributes.
Some elements of the draft guidance resemble a Six Sigma approach to manufacturing, which is familiar to the pharmaceutical industry. The main similarity is the draft guidance’s recommendation of a statistical link that demonstrates that variability remains constant from the clinical through the commercial manufacturing stages. The statistical link is intended to confirm that processes are the same throughout all phases.
Although the draft guidance suggests statistical analysis, it leaves industry with only a broad understanding of what that means. FDA does not explicitly suggest that manufacturers use particular statistical tools, the agency simply recommends that companies apply good statistics to establish the links, says Agalloco.
The draft guidance suggests manufacturers define a process that can be measured, analyzed, improved, and controlled, and this approach is closely related to Six Sigma. The benefit of the Six Sigma technique is that it provides a mechanism for scientific review of a process, for assessing variability, and for identifying improvements, says Ames.
On the other hand, it is unclear whether the draft guidance recommends a product be refined in the way that a Six Sigma approach would. “To me, Six Sigma implies an acceptance by FDA that you might not have done a sufficient job in development and scale-up and are allowed to improve product and process while it is in operation,” says Agalloco. Patients’ experiences with a product might persuade a manufacturer that it should adjust one of the drug’s parameters to improve it. Six Sigma would allow postcommercialization changes to a product, but the draft guidance may not be compatible with them, Agalloco says.
Before it could submit a regulatory filing, a company would have to spend a great deal of time and money to better understand its ingredients, its product, its manufacturing process, its material handling, and associated variables. Pharmaceutical companies might object to the draft guidance’s approach because it suggests this expensive work be completed before commercialization, but the costs would not be recoverable before commercial-scale manufacturing began.
Although it is based on good science, if the final guidance is approved as drafted, it could easily increase drug-development time by one or two years, thus costing a manufacturer millions of dollars, says Warren Charlton, a consultant at WHC Bio Pharma Technical Services. Manufacturers would need to use smart strategies to shorten development time, but not knowing how much data regulators expect in a submission would make this strategy difficult.
The draft guidance inspired a huge volume of comments that will likely take FDA a long time to review, says Agalloco. Even though the guidance might not be final for at least a year, manufacturers would be wise to study it now and seek advice about interpreting it. In this difficult time for the pharmaceutical industry, no company can afford to ignore regulators’ recommendations, and advance preparation would be to a manufacturer’s benefit.