Article

Validation Aspects of Solid Dosage Forms

R. Raghunandanan*
Pharma Consultant

Abstract
Validation is a huge topic and this article only provides an overall picture how validation for a solid dosage form manufacture should proceed given a facility and process. Excellent regulatory and general guidelines are available on the net and readers are encouraged to access them for acquiring more information. Beginners should use that information as a part of their learning and self training programme. Time and resources spent on validation are business investments and should be on the top of the agenda for a pharmaceutical manufacturer. Validation should not be taken as a regulatory compulsion, but a business requirement. Benefits of validation include reduction or even elimination of rejections and reprocessings, yield improvement and consistent quality in addition to regulatory compliance.

Introduction
Pharmaceutical industry has grown in leaps and bounds during the last three to four decades. Initial emphasis on validation started across the industry globally sometime in late sixties or early seventies. The concepts of validation first evolved in India in the early seventies. In the initial years the only emphasis was on massive testing of a large number of samples to establish that the process has yielded a product meeting the specifications. Indirectly it was thus concluded that the process was under control. Soon it was realised that this is not the right scientific approach. It was very clear that repeating a sterility test several times to get a passing test result was not only meaningless but jeopardizing to the patient too. Soon emerged several regulatory guidelines and publications on validation and today for the pharmaceutical industry successful validation is a pre-requisite. In this article we will limit our discussion only to the validation aspects of solid dosage forms, specifically tablets and capsules. Validation studies should be conducted against defined procedures and protocols. All the different elements of a pharmaceutical manufacturing process namely the facilities, the environment, the equipment, the people and the process should be validated against pre-decided validation plans. Recording of the plans, methodologies, observations, results and conclusions of the various experiments and exercises systematically is of paramount importance in validation. Good and robust documentation alone can demonstrate that validation has been done satisfactorily. *E-mail: [email protected]

Section 26 of the revised Schedule M of The Drugs and Cosmetics Rules in India stipulates that validation studies shall be conducted for processing, testing and cleaning procedures against pre-defined protocols. The section details various aspects of validation like documentation, periodic revalidation, prospective and retrospective validation, validation arising out of significant changes in manufacturing process etc. Thus it is mandated that the manufacturing processes are adequately validated.

areas, potent material segregation and separation, washing areas, utility areas etc. URS document should be as exhaustive as possible if disputes between user and supplier are to be avoided when the facility is ready for handing over to the user. Such a situation is counterproductive as well as detrimental to the business. Detailed drawing of the facilities should be prepared and approved in the early stages of the building construction exercise. Based on the agreed URS, a Design Qualification (DQ) protocol should be made for the facility. The various acceptance criteria should be defined in the DQ protocol. The construction of the facility shall be of solid structure using non-shedding materials. The materials of construction should be resistant to the various cleaning agents that will be deployed during the course of use and also to extremities in weather conditions. It should be remembered that in large tablets manufacturing facilities there will be a lot of large volume material movements and the quality of flooring in the dispensing areas, manufacturing areas, storage areas etc. should be in a position to withstand the same. In addition there are certain raw materials that stain the processing and washing areas and this inherent quality of the material could give un unacceptable appearance to the manufacturing areas. Suitable surface coating materials should be chosen to circumvent such inherent material issues. Doors and windows in the manufacturing areas should be flush type and easy to operate. One issue usually encountered in large manufacturing units is the manual

Facilities for solid dosage forms

Depending up on the magnitude of production, the manufacturing and related facilities will vary in size. Whether the facility makes few thousands of tablets or capsules daily or millions of the same daily, the basic principles of validation will remain the same. The performance of the facility where the dosage form is manufactured need to be demonstrated to meet both regulatory as well as in-house GMP expectations. A validation master plan should be generated first and foremost in line with the company's validation philosophy. The facility requirements should be defined in a URS (User Requirement Specification). This should take in to account not just area requirements and details of civil fabrics, but shall include even the minute details of men and material flow, general storage requirements, special storage requirements like temperature and humidity controlled

Pharma Times - Vol 41 - No. 4 - April 2009

15

movement of bins and churns within the manufacturing suites and also sometimes in and out of these areas and this leading to damages to floors, walls and doors. Suitable measure should be included in the design stage to avoid or at least minimise such damages over a period of time. Another important aspect of facility design for solid dosage forms is the requirements of flame proof areas in manufacturing. Though from an environmental point of view manufacturers either willingly or under compulsion are moving away from the use of solvents for tablet manufacture, there are circumstances where flammable solvents are unavoidable. Suitable flame proof materials and fittings shall only be used in such cases. Additional fire escape routes and emergency exits also should be taken in to account while considering the design of the facility. The Design Qualification stage should be completed by carrying out design verification and documenting that the various parameters are as per the agreed URS. A check list approach is useful sometimes. The objective is to ensure that all details are captured during verification and observations are documented. A DQ report should be made and signed off by Quality Assurance. It is a common practice sometimes to combine the DQ protocol and DQ report in one single document when facility (area) qualification is carried out. Whatever be the documentation the company follows, it should be ensured that there is good traceability for each parameter defined in the URS or design specifications and those observed during the qualification exercise and documented in the qualification report. The DQ of the area shall be followed by a formal Installation Qualification and Operational Qualification for any fittings like electrical fittings, fans, exhaust, alarms etc. and also fixtures like processing related furniture in the area. The Performance Qualification of the area is usually combined with the qualification of the HVAC system supplying to that area. Any changes that have taken place from the agreed URS, design specifications and pre-approved protocols should be assessed for its impact on the quality of products that will be made in the facility and handled according to the company's change control and deviation control procedures. These should be made part of the validation reports.

Qualification of HVAC system is one of the most important utility qualifications that need to be taken up first. As in the case of the facility there should be documented user requirements for the quality of air in the different areas of solid dosage form manufacturing. A design specification describing the various details of the Air handling System (AHU) should be available based on which a DQ Protocol should be prepared. The specifications should clearly spell out what room parameters are critical and what parameters are not, what are the contamination potentials, what stages of the process are closed operation and hence less susceptible to contamination etc. The Design Qualification Protocols should include details like AHU schematics, filter details like filter material, size, sealant details, material of construction of the filter frame etc., fan and chiller details, dehumidifying unit details, system monitoring details, operational control systems etc. On completion of the DQ stage, the validation team should move on to the installation of the HVAC system and complete the Installation Qualification stage. The IQ protocol should take in to account all installation parameters like electrical and mechanical fittings, availability of measuring instruments and gauges attached to the system. The next stage Operational Qualification stage involves checking of the operational parameters of the system like pressure drops across the various filters, motor operation, safety measures for fail proof running of the system etc. IQ and OQ reports should be prepared and signed off by Quality Assurance before Performance Qualification is initiated. The Performance Qualification of the HVAC system is a very critical activity to be completed as a part of the whole validation exercise. PQ Protocol should include parameters like HEPA filter integrity test, air velocity and air change rate, air pressure differentials, area temperature and humidity, non-viable particle count and viable particle count. The temperature and humidity should take in to consideration any product specific requirements. A Class D environment is what is generally expected in solid dosage form manufacturing areas where the product is exposed.

regulatory requirements consistently. The quality of water expected for use in solid dosage form manufacture is of Purified Water standard of the Pharmacopoeia. The water system should have a schematic representation and details like material of construction of the pipes and valves, slopes and dead legs, welding details for joints, UV tubes, online conductivity meters, sample points, user points etc. should be provided. Having established the design requirements for the water treatment plant a DQ should be performed to demonstrate that the plant and the distribution system meet the design specifications. This should be followed by an IQ to demonstrate that the plant and distribution system are installed satisfactorily. Stage wise qualification reports should be prepared and signed of by Quality Assurance. The Performance Qualification of the water system is done in three stages. The first stage PQ1 involves complete testing of water for all chemical and microbiological parameters from all the pre-decided sampling points for 14 to 28 days. At this stage water should not be sued for manufacture. If the results are satisfactory at this stage, the next stage PQ2 shall be initiated. In the PQ2 stage which extends from 14 to 28 days samples are tested from all the sampling points and water may be used for manufacture. The PQ3 stage extends to the next 11 months following PQ2 stage and would essentially demonstrate consistency over a period of the various weather conditions on the source of water. Reports should be made on completion of each stage and signed off by Quality Assurance.

Other Utilities
Other utilities usually involved in solid dosage from manufacture are steam and gases like compressed air and nitrogen. General principle of generating detailed schematic drawings and design specifications for in-house gas generators, distribution lines, on-line filters, end user points etc. should be followed and each utility should be appropriately validated. Documented evidence is essential to demonstrate that all product contact utilities are adequately validated and perform as expected. Gases should be demonstrated to be free from oil and grease, undue moisture content and excessive bio-burden. Appropriate specifications for particle counts in gases are also required depending up on the end use of the gases and risk involved in using such gases. Quality of steam used for direct product contact purposes like granulating solution preparation etc. should be such that the condensate meets the specifications for Purified Water.

Utilities - HVAC System

Along with the facility qualification the validation team could commence the qualification of the various utilities.

Utilities - Water System

Though water is usually not an ingredient in solid dosage forms, except in small quantities for aqueous granulation and aqueous coating, it is important to carry out validation to demonstrate that water system and water quality meet the cGMP and

16

Pharma Times - Vol 41 - No. 4 - April 2009

Equipment Qualification
Tablets and capsules manufacture involves use of several equipment at different stages of manufacture. Various stages of tablets manufacture like weighing, sifting, blending, granulating, drying, compressing, coating and packing involves several small, medium and large equipment and it should be ensured that there is a robust plan to qualify each of these equipment well in advance of commencement of manufacture. Criticality of each of the equipment involved should be spelt out and a risk assessment should be carried out by the validation team prior to commencement of validation. Each equipment should have detailed User Requirement Specification and the manufacturer or supplier of the equipment should be appraised in details about the user requirements. Discussions with the manufacturer or supplier of the equipment should start at an early date to avoid delays and ambiguities at the last minute. Involvement of representatives from user department, engineering, quality assurance and safety functions is imperative in addition to procurement department personnel. The company should organize for FAT (Factory Acceptance Testing) as soon as the piece of equipment is ready for dispatch. A detailed FAT by qualified engineers and user representatives will save a lot of time during the Design Qualification stage including the SAT (Site Acceptance Testing) once the equipment arrives at the site. Hence time and resources spent on conducting a detailed FAT is worth the money. Detailed DQ and IQ Protocols should be in place for each of the equipment and on completion of the qualification exercises DQ and IQ reports should be written and approved by Quality Assurance. Operational Qualification of the equipment should be carried out to establish and document the operational aspects of the equipment that directly or indirectly impact the product. During this stage the various controls associated with the equipment should be verified by qualified engineering personnel. A satisfactory OQ is a prerequisite before the performance qualification of the equipment is attempted which will also be part of the process validation for the dosage form. PLC based systems and other electronic system controls on process equipment poses a challenge during validation. Controls on testing the PLC based systems and other electronic systems should be carried out by well qualified personnel with the help of the technical team from the manufacturer or supplier of he equipment. It is usually a common practice to accept the documentation provided for this by the

manufacturer. However it is mandatory for the user site Engineering and Quality Assurance responsibility for reviewing and understanding the details of this and own accountability for the same. Computerised support systems are very common these days in almost all stages of manufacturing right from dispensing till the products are packed in to shippers. Detailed validation reviews and good validation documentation for each of these stages need not be overemphasised from a GMP and compliance point of view.

material manufacturer makes changes in the manufacturing process at his end. On several occasions it is a common practice to see that the raw material manufacturers make uncontrolled changes at his end without notifying the customer company and the customer runs in to processing problems. Process Validation Protocol should be written and approved prior to commencing validation. Pre-nominated batches (minimum three) should be taken for process validation. The process should go through each of the sub-processes like material loading, blending, granulation, drying, milling, sifting, compressing, coating etc. Details like machine settings, environmental conditions, step wise processing time and temperature etc. should be closely observed and documented during the validation exercise. Any deviation from the pre-defined parameters should be carefully reviewed and should be considered for adoption as a changed step in the process if adequately justified. Such changes should be reproducible in subsequent batches leading to a satisfactory output before they could be firmed up as part of the validated process. It is important to define batch sizes used for process validation and also the maximum and minimum operating limits or ranges. At the end all the three batches of the product should meet pre-approved product specifications for the validation exercise to be considered as satisfactory. Poorly controlled process could result in product not meeting quality parameters like content uniformity, dissolution, disintegration etc. Careful attention should be given to sampling aspects during validation studies. Extensive sampling than routine to get a better information of the effectiveness of the process step is always essential. This could be achieved by increasing the number of samples from a particular lot or batch, sampling during the process in a stratified manner, sampling at the beginning, middle and end of the process, layer wise sampling etc. Whatever be the methodology of sampling used, it should be documented in the process validation protocols. Testing of samples should be as per approved test methods and all samples drawn should be tested. A well planned in-process testing also should be designed as part of the protocols to track how the process progresses. The bulk tablet manufacturing should then proceed to the packing process validation. Though it may appear as a simple process, intricacies like sealing temperature could impact the product quality if not controlled adequately. Parameters like temperature and speed of the sealing roller during strip or blister packing, operation of counters during bottle packing, operation of weighing balances used for counter checking of bulk packs etc. should be included in the protocols. Other system that need to be validated will include under-fill detection

Process Validation
Once the facility is satisfactorily validated, all equipments and utilities are satisfactorily qualified the site should proceed for process validation. The objective of process validation is to establish and document that the defined process will consistently produce a product meeting the predefined specifications. Though unlike aseptically prepared products, processing of oral solid dosage forms may not appear to be challenging, the multiplicity of stages involved and impact of each stage on the final quality and effectiveness of the dosage form should not be underestimated. Oral solid dosage forms like tablets and capsules contain small quantities of active drug substance distributed in fairly large quantities of excipients and to ensure accuracy of the content of active drug substance and its uniform distribution, a robust process validation exercise is absolutely essential. A Validation Master Plan for the Process Validation should be generated at an early stage. The master plan should define in details the various steps involved in the manufacturing process and the criticality of each of these stages. Tablets and capsules manufacture involves various basic stages like sifting, dispensing, blending, drying, compressing and packing while additional stages like milling, encapsulating, coating, printing etc. could be product specific. Each step should be assessed for its criticality and these should be defined in the master plan. This way it will be easier to determine if an equipment or an environmental factor will affect the product. Inputs from experienced R&D personnel should be called for this exercise. If the product is an existing one, product history from data like annual product reviews, deviation reports etc. will be very useful. It should be borne in mind that quality of active and inactive raw materials especially the physical properties like particle size and particle size distribution, flowability, moisture content etc. could impact the quality of the product significantly. For this reason it is important to remember to carry out detailed validation reviews when sources of such raw materials are changed or even when the raw

Pharma Times - Vol 41 - No. 4 - April 2009

17

mechanisms, empty pocket detectors, seal integrity testing, bar code readers etc. Though cleaning validation is not intended to be discussed here, it should be remembered that no process validation exercise is complete without including effective steps for cleaning all the process equipments involved. Separate cleaning validation master plan and protocols should be generated and validation exercise carried out at the end of the processing. Safety aspects of handling potent and sensitive molecules during the process and subsequent cleaning operations should be considered and suitable safety precautions should be built in to the protocols and other operating procedures. These aspects should cover safety of both the personnel involved as well as the environment within and outside the unit where the materials are being handled.

Documentation
Any extent of validation exercise carried out will not be acceptable if there is no detailed supportive documentation attached

to it. The definition of validation includes the wordings "documented evidence" and the importance of good documentation practices to be employed during validation need not be over emphasised. The company's validation philosophy should be explained in a Site Validation Master Plan or Site Validation Policy. Next to the hierarchy of documentation will be process or facility specific Validation Master Plans. Various documents like User Requirement Specification, Validation Protocols etc. should be then generated followed by the Standard Operating Procedures. The principle "do what you write and write what you do" should be scrupulously followed throughout the validation process. Documents should be written as simple logical flows of each step to be carried out. While writing validation documents in good language (English as far as we are concerned) is very important, reviewers and approvers of documents should bear in mind that positioning of commas and semi colons should not lead to delays in releasing validation documentation unless these change the meaning of the text totally. After completing each stage like DQ,

IQ, OQ, reports should be made and approved by Quality Assurance before proceeding to the next stage. At the end of the PQ stage a detailed summary report should be generated and approved by Quality Assurance. The validation summary report should provide all aspects of the entire validation process and is the first document an auditor will review to get an idea of the process is under control. It is not very uncommon in industry to find very sketchy validation summary reports without adequate information and most importantly conclusions. Any deviations that arose during the process and details of how they were handled also should be included in the summary report.

Training
No validation will be a success unless the personnel involved in generating documents, carrying out the validation activities, reviewing documents and making final judgements are adequately trained. The company should have good training programmes for its staff handling validation activities and these should be documented.

IPA Building Construction Begins

Proposed IPA Building

IPA Building Fund

The President of Indian Pharmaceutical Association (IPA) appeals to all members of IPA to contribute minimum of Rs. 1000/towards the proposed IPA building at Mumbai. Kindly send your contribution through D/D or local cheque in favour of IPA Building Fund on the following address. Executive Secretary, Indian Pharmaceutical Association C/o. Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai 400098. All donations towards this fund will get tax exemption u/s 80G of Income Tax Act.

Appeal for

The construction of the IPA Building in Kalina, Mumbai, was initiated with a small puja on 10th April, 2009. The low - key ceremony was conducted by the contractors at the constuction site. Subodh Priolkar, Chairperson of the Building Committee, along with other committee members including S. D. Joag, Ram Banarse, Mohan Kekatpure, Dr. Alka Mukne & T. B. Nair participated in the porgram. IPA Maharashtra State Branch members Dr. Hemant Mondkar & Nitin Maniar were also present on the ocassion. The much - awaited building project is expected to be completed within the shortest possible time frame.

18

Pharma Times - Vol 41 - No. 4 - April 2009