Validation is one of the most regulated sectors of

Validationin the Pharmaceutical IndustryIntroductionThe Manufacture of pharmaceuticalproducts is a highly complex procedure and is one of the most regulated sectorsof any manufacturing industry. The original method of pestle and mortarof yester year have given way to highly advance and complex manufacturingprocedures of pharmaceutical products. What was once the preserve of a chemistor pharmacist are now controlled by computerized system. Due to the growth ofthe pharmaceutical sector fuelled by the demand for existing and new products,the methods of ensuring that all products that are released to the markets aresafe ,pure and effective for use by the general public have also developed Theregulatory requirement on the sector by such agencies as the FDA (USA), EMA(EU),MHRA (UK) and the HPRA (Ireland) have helped to ensure the high standardsof quality and met and so preventing the mistakes of the past.BackgroundThe history of RegulatoryRequirement in the Pharmaceutical Industry is a history of tragedy. At thebeginning of the nineteenth century there was very little if any Regulatoryrequirement for the manufacture of medical products.

Company would advertisetheir latest products some of which would contain substances such as cocaine,heroin, arsenic and oxalic acid. These products were hailed as a cure-all`s forall aliments and some were regularly given to children as in the case of opiumbased produces to help with teething. As a result of the tragedieFJ1 s it became clear that apath forward required to control the manufacture of Pharmaceutical productsthrough GMP  using  strong regulations and procedures. After eachtragedy stronger regulation was introduced to ensure FJ2 such mistakes may notre-occuragainFJ3 . The FJ4 pure Food and Drug Actand the Meat Inspection Act which were both signed into law on June 30th1906. This is widely accepted as the founding date of what is now the FDA. The ElixirSulfanilamide Disaster in the USA in 1937.Between the months of September and October 1937 Elixir Sulfanilamide was responsible for more than 75 deaths in 15 differentstates.

It was as a result of poor understanding of the chemicals usedand poor regulatory requirement for the testing of products before been releasedon to the market.The company Massergill and Co discovereda method to dissolve Elixir Sulfanilamide which wasvery difficult to dissolve using a formula containing diethylene glycol(antifreeze) and raspberry flavoured water this give it a nice appearance and asweet taste which would make it appealing to children. The new formula was sentto production and a week later released on to the market. Within week therewere reported cases of deaths due to the product.As a consequence of theSulfanilamideDisaster the federal government realised that greater regulation were required,this lead to the Food, Drug and Cosmetic act of 1938. Up to this point a companyFJ5  could not be prosecutedas was the case of Massergill and Co who were only charged with mislabelling ofthe product.With the introduction the Food,Drug and Cosmetic act (FDCA) companies were required to carry out safetytesting on their products and would be held accountable for any deaths orinjury caused by their products.

The goal of the Food, Drug and Cosmetic actwas to verify that the food, drugs and cosmetics were pure, safe and effectivebefore been released for general sale. The FDCA also ensure the correctlabelling and packaging of products  The Sulfathiazole tragedy occurredas a result of the Winthrop Chemical Company of NewYork released sulfathiazole tablets which were contaminated with phenobarbitalto the marketFJ6 , the resultwas hundreds of deaths and injuries. The FDA`s investigation revealed seriousplant control deficiencies and irregularities in the firm’s recall processes.As a result of the Sulfathiazoletragedy the FDA drastically revise their current rules on manufacturing andquality controls. The 1941 sulfathiazole disaster washailed as the birth of good manufacturing practices (GMP).Future amendments tothe FDC 1938 act were due to the Thalidomide Tragedy between 1953-1962  Thalidomide was  developed as a sleeping aid and given freelyto workers by Chemie Grunenthal , one worked give it to his pregnant wiferesulting in their child been born without ears. The drug was sold in over 40different countries.

In the USA FDA officer Frances Kelsey prevented the drugfrom been approved and resulted in prevent the same tragedy happening in theUSA. Shewas awarded President’sAward for Distinguished Federal Civilian Service fromPresident John F. Kennedy.

  GMPGood Manufacturing Practices Priorto FJ7 1970 the quality andsterility of products was only completeFJ8  at final producttesting. The Septicaemia outbreak of the early 1970`s in hospitals which wascaused Enterobacter cloacae of E.agglomerans due to improper sterilising of large volume parenteralresulting in 54 deaths. As a consequence of the FDA investigation whichresulted in total product recall and closure of the plant the FDA proposedchanges to the GMP`s which resulted in the introduction of GMP`s procedures  In 1976 the Medical Device Amendments wassigned in to law.

Thisgive FJ9 the FDA greater powersover medical devices. The FDA also Proposed changes to the GMP`s with a strong FJ10 emphasison the Sterilisation procedures used to sterilize manufactured products. It wasat this time that terms validation and Qualification began to be used withinthe pharmaceutical sector. In 1978 the cGMP`s rules final established theminimum current good manufacturing practices for the manufacturing process ,packing ,storage and transportation of medical products and devices. In 1979 Good Laboratory practicesGLPs (21 CFRFJ11 58) was established.

In 1980 the Infant formula Act waspassed into law due to the serious illness of dozens of children due to thelack of chloride in soy based formula. The Act give greater power to the FDA toenforce a minimum nutritional quality standard. In 1983 the Anti-Tampering act wasintroduced making it a crime to tamper with medical packing, this was a result oftampering with Acetaminophen capsules containers and the lacing of the capsuleswith cyanide. Also in 1983 better documentation was published to inspectcomputerised systems in drug manufacturing which was the beginning in computervalidation.The Therac Tragedy wasanother step along the road of GMP which was a result of software errors. Many valuablelessons were learned and better quality practice ware implemented to improvethe quality and testing of the software used in medical devices.In 2001 the EuropeanUnion (EU) published a set regulation called Eudralex. Eudralex are a set ofregulations that govern the manufacture of medical products for both human andveterinary use.

Eudralex consist of 10 volumes, volume 4 deals with GMP`s has19 Annex. Annex 15 deals with Qualification and Validation. Annex described themethod of qualification and validation of the facilities, utilities, equipment(FUE) and the process used to manufacture the medical product.

It also requiresthat the manufactures control all the critical aspects of the life cycle of theproduct and process through qualification and validation. Any changes in theproduct, process or FUE should be documented and assessed for its impact on thevalidated process. In 2015 an updated revision of Annex was published to takeinto account the changes in other sectors of the EUDRALEX.Along the long andtragic road that has led to the current point where the Pharmaceutical Industryis now one of the most regulated industries where GMP is something that isbuilt into every stage of the planning and manufacturing and wherequalification and validation are a critical part of every stage of the fulllife cycle of every product.

GMP regulatory is now a legal requirement forevery company wishing to manufacture medical products.ValidationQuality is very important in themanufacture of any produce sold today. But when that productFJ12 is a lifesaving products like Pharmaceutical products quality becomes even moreimportant. Quality is now a mandatory requirement by both Governments andRegulatory bodies. CGMP requires that quality be built in to the product atevery stage of its life-cycle.Validationis a documented procedure to provide assurance that a process reaches aspecified level of quality attributes consistently and be able to reproducethat consistently during all the different stages of the life of the product.  Process Validation is process tocollect data throughout the life-cycle of a product which provides scientificevidence that the process is capable of producing consistent high qualityproduct to ensure that it meets the regulation guideline requirements of suchregulatory agencies like the FDA and EMA. In the case of equipment validationit is referred to a Qualification.

  Inshort you validate a process but you qualify equipment.There are 4different types of validation.Prospective Validation ProspectiveValidation is validation done before distribution of a new process or anexisting process that may have had some changes made to it. The requirementsfor Prospective Validation is to provide documentary evidence that the processworks in accordance with the pre-prepared protocol and is normally completedbefore the product is released for sale and all the validation protocols areexecuted before the process is ready for commercial use.

At the productdevelopment stage the process is broken down into its own individual stepFJ13 s and each step is checked for its criticality tothe quality of the product. All the facilities, utilities, equipment (FUE) as wellas the test methods must be fully validated. The Master batch documents canonly be prepared after all of the critical parts of the process have beendetermined. This method of validation is the preferred approach and is the mostwidely used method of validationConcurrentValidationConcurrent validation is validationthat used documentary evidence to show that a process or FUE preformed the wayit is expected to, based on information gathered during the actual productionprocess.

This method measured all the critical steps within the process and endtesting and compared them to existing data to ensure the process is preformingas expected within the existing control parameters. An example of whereConcurrent Validation was used is during the Ebola disease outbreak wherevalidation is being done while the product is being manufactured. It is notusually allowed except in one off cases or as in the Ebola example where it isurgently required.  Retrospective Validation RetrospectiveValidation is a validation carried out on a well-established process usinghistorical documentary evidence to show that the process dose what it is meantto do and to the level expected of it. Retrospective Validation is only used onwell-established process where there has been no change to the raw material,FUE or the production process which are critical to the quality of the product.

Retrospective Validation should only be used where there is enough historicaldata to show that the process has being consistently producing produce thatmeet pre-established quality parameters. During the retrospectivevalidation samples, should be taken from all batches made during the validationperiod includingbatches FJ14 that have failed, the number ofbatches should be a large enough to show consistency of the process.  Revalidation Revalidationis used when there has been a change to any part of the process and FUE, it isused to determine the effect of the change on the process and FUE and decide ifrevalidation is required.

An example of revalidation is if a piece of equipment moving FJ15 for one location to another, revalidationwould be carried out to ensure that the equipment’s  acceptance criteria is met. Another examplewould be where maintenance work carried out and key components were changed, Revalidationwould be required before the equipment is returned to production.Differentstages of ValidationUser requirement specification (URS)  The URS isa document that described the requirements specification of a new process asrequired by the owner or end user. User Requirements Specifications are written by thesystem owner or end user typically before the validation process starts. The UserRequirements Specifications document is not intended to be a technical documentbut more a general description of the requirements of the intended process andshould be used as a reference throughout the validation life cycle.  Validationcan be broken down to several different stages which are called Qualificationsstages.Design Qualification (DQ) Installation Qualification(IQ)Operational Qualification (OQ)Performance Qualification (PQ)  Design Qualification(DQ)  It provides evidence that the URS requirementshave been met through FS/DS and any risks have been mitigated through FMEADQ is the design of the instrument it is not evidence of the URS beingmet, it is used to state the URS and the FS/DS and will show how the userrequirements will be tested .

Included in the DQ also ensures that any failuremodes are identified and will also be controlled in either the IQ/OQ of in anOP/procedure  InstallationQualification (IQ) Installation Qualification (IQ) provides documentary proof that theequipment or system has been delivered and installed in accordance with theinstallation specification documents and that the respective DS has been testedto ensure URS are met..   OperationalQualification (OQ) Operational Qualification provides documentary evidence that the FacilitiesUtilities, Equipment (FUE) and processed can consistency perform to the standard stated in theoperational specifications.  Testthat may be completed at this stage include and functional testing of theequipment  PerformanceQualification (PQ)FJ16  PerformanceQualification provides verification that the process can constantly produce aquality product over a certain period.

PQ is preformed when there are no down-streamchecks.      Benefits of Validation In the previous section, we have looked at theevolution of regulatory requirements leading to GMP for the production ofmedical products and how validation became a very important tool in thisprocess. We have also looked at the different types of validation and thedifferent qualification stages within validation Validationis a regulatory requirement but that is not the only reason that companypreform validation. There are a lot of benefits of validation some of them arelisted below. Reductionin production and quality cost.

Increasedquality.Reductionin lost time.  Reductionin the failure rate of product leading to lower rejection rate.

                                                                                           Increasedthe manufacturing capability by reducing failures and rework.Requiredless in-process and end-of-line testing.Can be usedto investigate invalids or deviation during production. Variationfrom batch to batch is minimized.

Bettercompliance with all regulatory agenciesOptimisationof the process and equipment.Betterscheduling of all required Maintenance.Improvesthe training of production staff and gives them a better understanding of theprocessesConclusionThe Pharmaceuticalsector is now one of the most regulated industries and safest. People haveconfidence that product`s or device are safe to use and will not have any majorside effects.

Regulatory guidelines provides a clearpathway for the manufacture of medical products. Validation is a key tool inproviding the quality assurance that is required to manufacture medicalproducts.