an overview of gmp

current good manufacturing practices

c k moorthy

an overview

an overview

current good manufacturing practices

c k moorthy

cgmp: an overview

Why is GMP so crucial? Just reflect for a moment. When didyou last pop a pill? Can you recall when you last administeredany medicine to your near and dear ones? Did it occur to you

at that time that the drug you were consuming or administering couldbe adulterated or misbranded? Did you consider having it tested to verifythat the drug was indeed what the label claimed it was? No? Don’tworry. You are not alone. Everyone does exactly what you did. Some,unfortunately, are no longer around to be counted.

Several patients at Davenport, Plymouth, UK paid for poorly sterilisedinfusions with their lives. Nearer home in Kolar, scores of hypertensiveand hyperglycaemic patients died because their medicines wereinadvertently interchanged at the manufacturer’s end during packagingand labeling. Little children on multivitamin courses developed severe

6 current good manufacturing practices

reactions because of cross-contamination with a systemic allergenproduced earlier in the same equipment train. Suffice it to say that theroad to CGMP as we know it today is paved with the graves of innocent,trusting patients!

Disasters like these are rare, which explains your own complacency andblind trust in the pharmaceutical industry when you consumed yourpill; but, disturbingly, they are not uncommon. Contrary to what youmay have thought, drugs are not produced by infallible super humans inouter space. Veterans in the industry certainly recall lapses theythemselves have witnessed over the years. Fortunately, most suchblunders are discovered or detected in time before they leave the factoryand reach the consumer.

Current Good Manufacturing Practice (CGMP) endeavours to addressthese issues.

what is gmp?

CGMP is a quality system of, by and for the drug and device industries,unlike ISO and other quality systems which are generic in nature. Itrecognises that any manufacturing organisation has three distinctiveaspects or elements: its resources (21CFR211 sub-sections B, C andD); its manufacturing process (21CFR211 sub-sections E, F and G);and its Controls (21CFR211 sub-sections H, I, J and K). Hence, CGMPmay be defined as:

“a quality system that seeks to demonstrate with documentedevidence that the manufacturer has harnessed these threeaspects or elements of his Organisation harmoniously toeffectively deliver the drug or device that consistently,repeatedly and reproducibly meets or exceeds the quality,purity and other characteristics which it purports or isrepresented to possess.”

In some countries CGMP is merely a guideline; but in most others itcarries the weight of a law. Laws exist to safeguard some right or corevalue of a citizen, and CGMP is no different.

core values

WHO, European, Indian and other Regulatory Agencies advocate thefollowing core values in a drug product or drug substance: Safety, Efficacyand Quality.

7an overview

Though Material Safety is already established through exhaustive andconclusive non-clinical safety and toxicity studies in GLP recognised testfacilities; and Efficacy is proven beyond reasonable doubt in multi-phasedclinical studies in GCP environments, the Regulators still seek reassuranceat the drug or device manufacturer’s end that he is doing all that needs to bedone to protect and promote such established safety and efficacy of thematerials he handles from receipt, through processing till final delivery tothe patient.

The USFDA CGMP aspires to protect the patient with the same corevalues; but labeled differently:

Safety : The product remains free of any unexpected side effectswhen used appropriately

Identity : The product is exactly what the label and related materialsay it is; every material, component, significant piece ofequipment and operation is labeled and documented sothat lot histories can be accurately reconstructed fromstart to finish

Strength : The concentration of the drug substance (for example,weight/weight, weight/volume, or unit dose/volumebasis), and/or the potency, that is, the therapeutic activityof the drug product as indicated by appropriate laboratorytests or by adequately developed and controlled clinicaldata (expressed, for example, in terms of units byreference to a standard)

Purity : Absence of substances that produce adverse effects onthe product

Quality : Fitness for intended use

This is due to their recognition that Efficacy could be seriouslycompromised if there is any doubt about the Identity, Strength or Purityof a drug placed in the market. For example, if the Purity is compromised,it automatically alters the Identity of the drug product or drug substance,rendering it both adulterated and misbranded, thus placing the patientat risk.

areas of concern

Drug or device production has four, and just four, primary areas ofconcern that could potentially place a patient at risk:

Contamination : Any substance or energy that adverselyimpacts upon drug/device performance


Goof ups : Errors of omission and commission ofhuman origin

Mix ups : Special case of human error throughgross negligence and carelessness

Process inconsistency : A process that is unstable, unreliable andincapable

All regulating authorities around the globe share these core values andconcerns. In fact, Inspectors, when faced with an unusual situation, areencouraged to apply the same risk analysis technique to assesscompliance. The approaches they adopt for enforcement, however, candiffer.

For example, the US FDA makes its position clear with the followingdefinitions and explanations:

Drug: Articles intended for use in the diagnosis, cure, mitigation,treatment, or the prevention of disease in man or other animals. Articles(other than food) intended to affect the structure or any function of thebody of man or other animals; and articles intended for use as acomponent of any articles specified above.

* A drug is deemed to be adulterated if the methods used in, or thefacilities or controls used for, its manufacture, processing, packingor holding do not conform to or are not operated or administered inconformity with cGMP to assure that such drug meets the...qualityand purity characteristics which it purports or is represented topossess.

* Prosecution under “unique legal doctrine” that does not requireproof of criminal intent as a pre-requisite for criminal culpability -neither requires that actual harm from contamination of a drugproduct has to be proven for a charge that the product is adulterated,nor that each article in the batch be adulterated before the entireamount is subject to condemnation or other action.

In stark contrast, we have the WHO, who believe that

* The risk of rejection is inherent in any process

* Each step of the manufacturing process must be controlled to minimisethe likelihood that the finished product will be unacceptable

* Quality cannot be inspected or tested into a product

* Quality, safety and effectiveness must be designed and built into aproduct

9an overview

WHO has always stood firmly behind the need for Quality Systems toguarantee “Safety, Efficacy and Quality” of drug products. . The EuropeanCommunity, and our own Schedule M, echo these sentiments as well.

Let us not forget that it was WHO that first launched the GMP initiativeway back in 1967. The first World Health Organization (WHO) drafttext on good manufacturing practices (GMP) was prepared at the requestof the Twentieth World Health Assembly (resolution WHA20.34) in 1967by a group of consultants. It was subsequently submitted to the Twenty-first World Health Assembly under the title “Draft requirements for goodmanufacturing practice in the manufacture and quality control of drugsand pharmaceutical specialities” and was accepted.

The revised text was discussed by the WHO Expert Committee onSpecifications for Pharmaceutical Preparations in 1968 and publishedas an annex to its twenty-second report (1). The text was furtherreproduced (with some revisions) in 1971 in the Supplement to the secondedition of The international pharmacopoeia.

When the World Health Assembly recommended the first version of theWHO Certification Scheme on the Quality of Pharmaceutical ProductsMoving in International Commerce in resolution WHA22.50 (1969), itaccepted at the same time the GMP text as an integral part of the Scheme.

MCA’s first Orange Guide was published in 1972, after the Davenportdisaster; and US FDA’s CFR 210 and 211 were released only in 1978.

Regulatory expectation levels and enforcement stringency are not uniformfor all drug products or constituents. A general ranking is given herefor formulations:

O Research compounds, allergenics, toxicsO Sterile products and their processes1 Large Volume Parenterals (LVPs) 100ml -1000 ml2 Small Volume Parenterals (SVPs) 1 ml - 100 ml3 Opthalmics, other sterile products, medical devices4 Non-sterile products and their processes

a Low-dose/high-potency tablets and capsulesb Metered Dose Inhalersc Transdermal Delivery Systems (TDDs)d Drugs with stability problemse Other tablets and capsulesf Oral liquids, topicals, and diagnostic aids


Table 1: Application of GMP to API Manufacturing

For Bulk PharmaceuticalChemicals, mostRegulatory Agenciesfocus on only the ActiveProcess Ingredient; onlyWHO has includedExcipients under theGMP umbrella.

GMP expectationsremain vague for somecategories of productsl i k eradiopharmaceuticals,where half-lifeconstraints limit theapplication of GMP

The full GMP Canvas

EUGGMP

WHO

Figure 1: GMP as a Quality Philosophy vsGuidelines & Regulations

USFDA

Schedule M

11an overview

protocols in their entirety. While some guidance is available for biologicalproducts, it is woefully inadequate, and does not take into full accountthe very special and hazardous nature of these products.

All the Regulatory Guidelines are not alike in their expectations. Whilethere are large areas of common agreement, there are still differences inthe fringes. As a consequence, any organisation that aspires to fullymeet with just one such guideline may find itself short when measuredagainst some other guideline.

regulators’ rationale

Why is there such variance in their respective expectations? Tounderstand this, we must examine the philosophy that guides theseagencies in drafting their regulations, and the role they play as regulators:

* Weighing Risk vs Benefit, rather than Cost vs Benefit

* To balance the need for precise, easily understood standards, whichease both compliance and enforcement burdens, with the need toencourage innovation and the development of improvedmanufacturing technologies

* To provide manufacturers with the discretion on how to achieve thelevel of control necessary under GMP, recognising that in a fewinstances, more discretion from the agency is necessary because ofthe potential harm, the narrow range of acceptable means toaccomplish a particular cGMP objective, or to provide a uniformstandard to the industry

* Recognising that the cGMP regulations would not achieve theirstatutorily mandated purposes if they were not periodically reassessedto identify and eliminate obsolete provisions or to modify provisionsthat no longer reflect the level of quality control that currenttechnology dictates and the majority of manufacturers have adopted.

* A GMP regulation is intended to be general enough to be suitable foressentially all drug products; flexible enough to allow the use ofsound judgment and permit innovation; and explicit enough toprovide a clear understanding of what is required.

* A practice is adopted as GMP if it is feasible and valuable incontributing to assurance of consistency and homogeneity in productperformance or value

* To consider a practice GMP, it is not a pre-requisite that it be actuallyin use by a majority, or even a specific percentage of the Industry


* A practice must be “current” and “good”. And to stay in compliance,practices must be continually updated. When and whether are mattersof sound judgment influenced by the drug preparation underconsideration.

how much compliance is enough compliance?

Adherence to the explicit regulations is a required minimum, but itis not adequate to ensure compliance.

In other words, the Regulators view full compliance with their regulationsas bare minimal expectation from any drug or device manufacturer, andencourage each to aspire to provide greater safety, efficacy and qualityin the products offered to the patient.

compliance reality check

As the twentieth century drew to a close, there was, amongpharmaceutical regulators in the developed world, specially in theUS, a growing sense of unease that something was seriously amiss inthe industry in terms of its quality, productivity and costs. While allother industries had forged ahead, the pharmaceutical industry waslagging behind in terms of technology and efficiency, trapped in somekind of time warp. In the words of Dr Ajaz S Hussain, USFDA, “Thepharmaceutical industry has a little secret: even as it invents futuristicnew drugs, its manufacturingtechniques lay far behind those ofpotato chips and laundry-soapmakers, who all have better controland better understanding of theirmanufacturing processes than domost pharmaceutical companies.”

This sentiment was echoed by severalothers, including the Wall StreetJournal, which carried a cover pagearticle stating that the prevailingregulatory environment was forcingmanufacturers to ship jobs overseas,since continuing in US wasincreasingly unviable. For example,manufacturing costs inpharmaceuticals is a startling US$ 90

Figure 2: The “crisis”

13an overview

billion, far in excess of its research investments.

Once this recognition sunk in, the USFDA lost no time, spared no effortand left no stone unturned in its quest to remedy this sorry state ofaffairs. Expert Work Groups were set up, committees were put in place,suggestions were solicited from industry and academia – to identify whatall was wrong, why and how to set things right.

background to the current state

In order that we may better appreciate the situation as it has prevailed,it would help if we could first learn why, and how, it got to be so in thefirst place.

insecurity

The USFDA’s position has always been:

“A drug is deemed to be adulterated if the methods used in, orthe facilities or controls used for, its manufacture, processing,packing or holding do not conform to or are not operated oradministered in conformity with CGMP to assure that suchdrug meets the requirements of this Act as to safety and hasthe identity and strength, and meets the quality and puritycharacteristics, which it purports or is represented to possess.

“Prosecution under “unique legal doctrine” that does notrequire proof of criminal intent as a pre-requisite for criminalculpability - neither requires that actual harm fromcontamination of a drug product has to be proven for a chargethat the product is adulterated, nor that each article in thebatch be adulterated before the entire amount is subject tocondemnation or other action.”

While it is fine as statements of “law”, it strains the relation betweenthe Inspector and the Inspectee. Undercurrents of mutual suspicion andmistrust are inevitable, and the inspectee’s defences are forever on ahigh. The industry’s primary aim has been to be in a state of preparednessto survive the next Inspection.

differing takes on what the acronym “GMP” actually meant

Thirty years ago, FDA’s emphasis was on institution of basic procedures,including Testing to document quality, and record-keeping, which evolved


to CGMP of today. The testing and documentation stayed on, aroundwhich a QA group was built, and somehow the “quality” part got lost;and QA became more based on documentation than on quality, anddifferent stake-holders had their own take on what GMP meant:

Management Give Me Profit!

Marketing & Finance Give Me Production!

Regulator Give Me Proof!

QA Give Me Paper!

rules of the regulator and the regulated

USFDA also has always had its rules and theories regardingdocumentation, and QA (wryly referred to in some circles as Departmentfor “Quiet Adjustments”!) responded with its own corresponding set ofcorollaries and interpretations:

Regulator’s Rule 1: If it is not written down, it didn’t happen. It’sjust a rumour!

QA’s Interpretation: If it is written down, Inspector will accept it asproof that it actually happened! So all you needto do is to just write it down!

Regulator’s Rule 2: If it is not written down properly, it didn’thappen properly. You can never be certain as towhat actually happened!

QA’s Interpretation: If it is written down properly, Inspector will besure as to what happened, and believe that ithappened properly! So, see that you write itdown properly!

Regulator’s Rule 3: If the records are not correct, so is the product!

QA’s Interpretation: If the records are correct, Inspector will presumethat the product is also correct! So just ensurethat your records are correct.

This led to the GMP (Generation of Mountains of Paperwork) we havebeen routinely witnessing in the industry ever since. CGMPs werereduced in practice to Clever Guileful Mal-Practices (or Complete GolMal Practice!): Manufacturers produced two products: one for the patientthat was sent to the market, and one for the FDA (full of paperwork).

15an overview

One manufacturer in Australia had perfected all this to a fineart! The deception went undetected until someone, hallucinatingthat his plane was on fire, frantically tried opening an aircraftdoor at 30,000’ to jump out, and triggered an investigation byTGA that discovered a can of worms!

if it ain’t broke, don’t fix it!

The Agency wanted you to “Say what you do, and Do what you say”.The DMFs and SOPs declared what you do; and your records showedyou did what you said. Along came the era of validation when you wererequired to demonstrate with documented evidence as proof that yourprocesses actually worked as intended. A process once validated wasrequired to be maintained in a high state of control, and evidence of thismust be maintained. For post-approval changes, the legal position is:

The applicant must notify FDA of each manufacturing change inaccordance with section 506A of the Federal Food, Drug, andCosmetic Act and, when finalized 21 CFR 314.70 (CDER) and514.8(CVM).

An applicant must inform the FDA about each change in the product,production process, quality controls, equipment, facilities,responsible personnel, or labeling established in the approved licenseapplication(s) (CBER 601.12)

The applicant must assess the effects of any change on the identity,strength, quality, purity, and potency of the drug as they may relateto the safety and effectiveness of the drug before distributing productmade with the change (Section 506A of Act, Section 116 FDAMA).

With the all-numbing fear of regulatory penal action hanging like theproverbial Damocles’ sword over the industry’s head, none would wish toattract undue attention or risk regulatory incursions by advertising“innovations” or “improvements”, when managing “deviations” and“changes” themselves were a handful. Quite naturally, “If it ain’t broke,don’t fix it” was the unwritten dictum; and “Let sleeping dogs lie!” theabiding rule. As a matter of fact, it is not uncommon in the industry to findthe caveat: “Don’t use COMMONSENSE in place of SOP!” Where’s theroom for good old commonsense in such a stifling environment anyway?

confusing interpretations

EUGGMP / WHO: “Alternative approaches are permitted if they arevalidated and provide equivalent levels of quality assurance”


TGA: For the purposes of this Code, the words “should” and “shall”appearing in each of the Chapters 1 to 9 inclusive in the Code, and ineach of the Annexes 1 to 17 inclusive in the Code, mean “must” and theactivities, descriptions or specifications accompanied by the word“should” or “shall” are to be read as mandatory, unless the manufactureris able to demonstrate that the activity, description or specification isinapplicable or can be replaced by an alternative which must bedemonstrated to provide at least an equivalent level of quality assurance.

USFDA on “Guidance”: Are manufacturers required to adhere toguidance? No. But if they are put out by the FDA, it is likely theinvestigator will find adherence to the guidance generally acceptable

Significance of the phrase, “where appropriate”: 820.1(a)(3): In thisregulation the term ‘‘where appropriate’’ is used several times. When arequirement is qualified by ‘‘where appropriate,’’ it is deemed to be‘‘appropriate’’ unless the manufacturer can document justificationotherwise. A requirement is ‘‘appropriate’’ if nonimplementation couldreasonably be expected to result in the product not meeting its specifiedrequirements or the manufacturer not being able to carry out anynecessary corrective action.

investigation findings

regulatory woes

O Regulatory uncertainties inhibit innovations or improvements

O The rigidity and zeal of Regulatory Agencies to enforce, and theextreme anxiety in Industry to remain in compliance, has sadlycombined to create a climate of uncertainty that has served as a lid,rather than ladder, to Quality in Pharmaceutical Manufacturing.

O FDA’s aversion for and mistrust of statistics and statisticalmethods inhibited industry’s application of Statistical ProcessControl methodologies

industry woes

Dr Janet Woodcock summarised the shortcomings in the industrysuccinctly:

• Inability to predict effects of scale-up

• Lack of agility –usually takes years to bring up a new production site

• Operations fragmented around globe

• Inability to understand reasons for manufacturing failures

17an overview

quality system

CGMP as a Quality System, when compared with the Quality Systemsemployed by other, successful, industries, was superior in some instances,but had some serious deficiencies as well:

• CGMP do not incorporate explicitly all concepts found in a modernquality system

• CGMP are Regulator-driven (push): other QSs are Management and/or customer driven (pull)

• No requirement for management to lead, commit to, support or reviewthe Quality System

• No requirement for a Quality System – only Quality Unit functionsare required

• No requirement for Continual improvement of the quality system

• No requirement for Continual improvement of process and productimprovement

• Limited proactive approach (especially with preventive actions).While the industry did practice CAPA, it waited for things to gowrong before reacting, and seldom anticipated what may go wrongand use CAPA for taking proactive action for prevention.

quality

O Materials not well characterised; process factors not wellunderstood; cause of variability not well investigated; developmenttrials treat process as uni-variate systems

O Processes are held in a state of control, but little knowledgeavailable about why or how they managed to attain that state

O Enormous data collected, but little analysis, or efforts towardsconversion of data to meaningful information or knowledge

This is attributable to the archaic definition of Quality that prevailed.

When the “Quality” epidemic swept the globe, there were as manydefinitions of the term as there were gurus preaching it. Thepharmaceutical industry selected Juran’s: “Fitness for use”.

The ICH expanded this to:

“The suitability of either a drug substance or drug product forits intended use. This term includes such attributes as the identity,


strength, and purity” (fromICH Q6A Specifications:Test Procedures andAcceptance Criteria forNew Drug Substances andNew Drug Products:Chemical Substances).

Others who had opted for thesame definition soon discardedit as inadequate. For example,automobile transmission manufacturers in the US incurred three timesas much by way of warranty costs as compared with their Japanesecounterparts; and the reason turned out to be the wider variability incritical dimensions in the former’s process.

The modern definition is that “Quality is inversely proportional toVariability”, and “Quality Improvement” is defined as “the reduction inthe variability of processes and products” (or just “reduction of waste”).In other words to control Quality of a process, one must focus onidentifying, controlling and reducing all those factors that contribute toits Variability.

Hence, the revised definitionof pharmaceutical “quality”states:

Degree to which a set ofinherent properties of aproduct, system orprocess fulfillsrequirements

poor productivity

Professor G K Raju, MIT,carried out an investigationalsurvey and presented hisfindings to the FDA ScienceBoard on some of thepossible reasons for such highcosts and wastes, and thecrying need for fundamentaltechnology and administrative

Figure 3: What is Quality

Figure 4: Production cycle

19an overview

changes: Archaicmanufacturing technologies;poor production efficienciesand utilisation; largewastages; high costs ofmanufacture and compliance.

Wastage of time and resourcescan be found from the timeraw materials are ordered tothe time the drug reaches thepatient and the industry didnot seem to care. In fact, thegeneral perception in theindustry is that Quality andProductivity cannot coexist -one comes at the cost of theother.

Professor Raju dwelt at lengthon the protracted productioncycle times, and pointed outthe marked tendency to livewith a “validated” process,rather than resolve a known process problem, producing almost as manylots with exceptions as those without. Often the time taken for QC testingand approval exceeded the manufacturing time several-fold. In a particularstudy, he observed that average cycle time was around 95 days, with astandard deviation of about the same duration, and this gets further impactedby over 50% in the event of an OOS result!

With such low capacity utilisation, he stressed the need for fundamentalchanges in manufacturing and testing technologies.

poor prioritisation

While ABC classification was a common feature in other industries tohelp focus on the important few, rather than fritter away resources onthe less significant many, there was no such comparable practice in thepharmaceutical industry. Risk Management was principally confined toSafety related issues, not applied to quality management or operations.For example, there was no distinction on issues, and all were beingtreated with the same rigour and due process: whether it was a deviation,change, or even an indent to procure an item - there was no categorisation

Figure 5: Production Delays


as “A” (critical), “B” (moderately critical) or “C” (minor). This wastrue for the Agencies as well, where the Regulator would treat allformulators alike in matters of oversight, without regard to how criticalthe formulation was for the patient, or its availability in the market orthe manufacturer’s past track record with respect to GMP complianceor adverse events in the market. All this was only adding pressure oncosts, time and scarce resources.

recommendations for The “desired” state

The Think Tanks carefully articulated their shared vision for the 21st

Century, what they fondly described as the “Desired State” of affairs tobe attained, both for the Industry as well as the Agency.

O Barriers to continuous improvement to be reduced or removed

O Create an enabling environment to promote innovation by

- removing regulatory fear/uncertainty

- utilising science and risk based approach to oversight

- flexible and less burdensome approach for well understoodprocesses

- facilitating rational science, risk and business decisions

O A maximally efficient, agile, flexible pharmaceuticalmanufacturing sector that reliably produces high-quality drugproducts without extensive regulatory oversight.

O Sustained and improved product quality and performance achievedand assured by design of effective and efficient manufacturingprocesses

O Specifications based on parameters that truly impact product quality- through mechanistic understanding of how formulation and

process factors impact product performance

O Common understanding and language on risk. Both, industry andcompetent authorities focus on areas of greatest risk andunderstanding of residual risks

O An ability to effect continuous improvement and continuous “realtime” assurance of quality

To set in motion the Transformation Agenda, a PAT (Process AnalyticalTechnologies) team was set up in 2001; the 21st Century GMP Initiativewas up and running in 2002; and the Critical Path Initiative was inplace in 2003.

21an overview

As draft reports began trickling in, the USFDA realised the need toenlist the support of their counterparts in EU and Japan. Crack teamswere dispatched to meet with them and discuss these “revolutionary”ideas. The mission was a total success. ICH Expert Working Groupswere set to work on harnessing risk-based concepts and principles forQuality by Design (Q8), Quality Risk Management (Q9), and Life-cycleapproaches to Pharmaceutical Quality Systems (Q10) with ASTMcommissioned to develop standards for the emerging needs of advancedmeasurement technologies.

The whole exercise is aimed towards ushering in a change in behaviour:from tick-box compliance to scientific, rational, risk-based thinking,focusing on things that matterto the patient.

In the words of the group thatsubmitted its final report andGuidance on ProcessAnalytical TechnologiesFramework:

“At the end of the CGMPInitiative the pharmaceuticalcommunity has arrived at across-road; one path goestowards the desired state andthe other maintains thecurrent state. The pathtowards the desired state isunfamiliar to many while thecurrent state provides thecomfort of predictability. TheAgency hopes thepharmaceutical communitywill choose to move towardsthe desired state.”

current status

ICH Q8, Q9 and Q10 havebeen adopted to change themind-set and approach of theindustry from a tick-box cultureto one that is more science and

Figure 6: QRM driven process

Figure 7: New Quality System


Figure 8: Management-centric Quality System

Figure 9: ASTM E 2500 - Verification by Subject Matter Experts

23an overview

risk-based; a Quality System has been proposed, similar to the one alreadyin existence in the medical device industry, to have a management-led andmanagement-driven Quality Culture that has at its core a “main qualitysystem”, around which revolve satellite “sub-systems” to encourage differentgroups to take responsibility for quality in their respective turfs; ASTM E2500 is in place since 2007 that rejected the sequential and ineffective DQ/IQ/OQ/PQ approach to Qualification of buildings, facilities and equipmentand replaced it with a more comprehensive science and risk-basedVerification by Subject Matter Experts; and based on all these documentsthe new Process Validation Guide was released by USFDA in 2011, withEUGGMP in the process of aligning its Annexure 15, which has totallyreplaced all existing concepts of pharmaceutical validation and promotesProduct Quality Life-cycle Implementation beginning with quality by designand continual improvement backed by continued verification.

Each of these path-breaking initiatives is aimed at reducing the chronic“waste” of time, materials and other resources that has been plaguing theindustry, and place it on a fast track to greater quality and productivity.

progress in adopting 21st century GMP initiatives

The pharmaceutical industry has no great reputation for embracingchanges swiftly. It took the USFDA almost a decade to get their first

Figure 10: Product Quality Life-cycle Implementation


major conviction. It took more than a decade, with much insistence andcajoling, to get pharmaceutical validation off the ground. It is over fiveyears since QbD, QRM and ASTM E 2500 were released, but the changesmooted are yet to gain widespread acceptance. The focus of QualityAssurance continues to be on survival of Inspections and Audits;management-driven Quality System culture has not taken root; and themuch expected change to science and risk based approaches to qualityand productivity is yet to materialise.

Yet I am optimistic. The industry is slow to move, but is not, and hasnever ever been, at standstill. It may be tardy, but it still is dynamic, notstatic. It may take five more years, or even longer, but eventually each ofthe manifold bold initiatives will bear fruit. And when that happens, thebiggest beneficiary of all will, and much deservedly, be the Patient!

beyond regulatory compliance: towards GMP as a culture

How should you approach GMP? Meet norms? Whose norms? Asalready mentioned earlier, meeting one set of norms may leave you belowthe expectations of some other norm. Even if you take the sum total ofall norms and guidelines, they collectively still represent the “minimal”set of practices and expectations that constitute GMP, not the “maximal”.The canvas of GMP is vast, and as explained above, not all such practicesfind their way into the Guidelines, for various reasons.

Now about cGMP compliance. Remember that “Compliance” means“obedience”; and “Regulatory Compliance” refers to initiatives calculatedto appease the regulatory gods. For as long as this is your sole motive,all your GMP efforts will remain sub-optimal.

Compliance is all about meeting norms. These norms can be approachedin one of two ways: from beneath, where norms appear as the ceiling; orfrom above, where norms represent the floor. The former approach isregulatory-driven compliance; the latter is culture- driven. Current andemerging regulatory expectations keeps practitioners of the formerapproach running to stay in the same place, while practitoners of thelatter approach remain protected in a cocoon of comfort.

All great “leaders”, organizations, individuals, regardless of the industryor profession they represent, have one link in common: they follow codesand disciplines that are largely self-imposed, and usually ahead of theirtimes. This is what empowers and emboldens them to tread new grounds,blaze new trails and set new precedents. There is no discipline like self-discipline; no help like self-help.

25an overview

Any practice, before it finds its way to a Regulation, is first adopted bya “leader” in the industry, as part of his “real” compliance program,who demonstrates that it is not only superior to existing alternatives,but also raises the level of confidence of producing fewer defectives.

Hence, actual practice always precedes its incorporation into anyregulation. What you see as “regulation” is actually history of someachievement long past.

The “leader” has since raised the bar even higher, nudged the frontierseven farther. Which explains why he is always in a zone of comfortwhen it comes to regulatory compliance.

Compliance confers the following benefits, regardless of the approachtaken:• Product equivalence• High-quality products• Reduced regulatory burden• Expedited drug approval• Reduced time to market• Low rework, rejection and recall rates

In the pharmaceutical and biotechnology industries, highly “regulated” asthey are, the approach towards compliance is predominantly “regulatory”:

• Understand and follow GMP regulations• Validate manufacturing processes

Standards,Guidelines,

GMP

Users &Vendors

Regulatory Authority

Figure 11: The GMP cycle


• Implement effective master and batch production and controlrecord systems

• Develop written procedures for critical process and control steps• Provide employee training programs

Regulatory Compliance is conditional and its aim or goal or purpose ispurely to satisfy regulatory requirements, achieve satisfactory inspectionaloutcome and avoid regulatory citations. On the other hand, when youdo things as a matter of Organisational culture or tradition, exceedingnorms is not an unusual phenomenon. It is unconditional and the solepurpose is to achieve and sustain a high state of control. While thoseaspiring for regulatory compliance follow procedures laid down by others,the leaders design, implement and control their own procedures; validateand document critical processes and operations based on sound scientificprinciples and best technical practices

The results are that the former group can at most achieve a state of GMPwhich is reactive and unstable; which can easily be upset by changes inregulations and guidelines; where employees must be frequently retrainedon changed systems and procedures; which is influenced by latestinspectional trends and citations. Compliance here is a dependentvariable: depends on compliance with current regulations.

In contrast, wherever GMP is embraced as a gospel, there is automaticregulatory compliance, a high state of control, continuous improvementin operating and control systems, continual updating of skills andknowledge. It is proactive, independent of external trends andindependent of cGMPregulations andguidelines current oremerging. Suchorganisations operate ata higher level thancGMP, and well aheadbecause they operate inan environment with:

– a higher state ofcontrol designed into it– a science andtechnology base– an effective control &information system

GMP as Culture

The full GMP Canvas

Sum total of allRegulatory

Expectations

Where you want to betomorrow

Where you are today

Figure 12: GMP as culture

27an overview

“Observing Traffic Rules is a sign of civilisation” comments a hoardingin Egypt. “Aim for the moon and you might still hit the tree tops”,quipped an old friend. These represent my sentiments.

We in India remove our footwear at the entrance; wash our hands beforeand after a meal; bathe at least once a day. Women are advised to stayisolated during their menstrual periods. No one has to tell us to do that;we do it by sheer force of habit. Because it is our tradition, our culture.Such acts are not so common or widespread in many parts of the world:they need to be told. GMP is more compatible with our culture thanwith many others’. Make GMP your culture, and you will never be outof compliance.

make the drug as though it is for your own

Regulating Agencies everywhere urge each person engaged in drugmanufacture to act as they would if they knew that it was being made forone of their own family members. When your own child is in pain, andyour physician is temporarily unavailable to visit you and gives youdetailed instructions over phone to prepare a home remedy that wouldprovide relief till he can come over, you never abdicate your responsibilityby delegating to someone else, no matter how busy or pre-occupied youmay be at the time. You drop everything you are doing, prepare thepotions yourself and attend to your sick child. If you can show half asmuch dedication in your workplace as you do when tending to yourchild, every one of your patients will forever be safe!

role of quality control laboratory in GMP

Since this book is also written for those in pharmaceutical quality control,it is both necessary and relevant to highlight their role in compliance.The Regulators are keen to protect and promote the core values of Safety,Efficacy and Quality of drug substances and drug products entering themarket. Since they are not physically present at each manufacturer’spremises to oversee operations, they have entrusted this responsibilityto the group within that Organisation called QC: to serve as a bufferbetween Vendors and Production and ensure that components allowedto enter the process bear the requisite quality characteristics and do notplace the process at risk; and as a buffer between Production and thePatient, making sure that shoddy products never leave the door, so thatno patient is ever put at risk. Such implicit trust is a huge responsibility,and calls for the highest level of integrity and professioanl excellence inthe discharge of your duties.

Judge yourself by how much GMP you can practise,Not by how much GMP you can preach!

Figure 13: Ten Principles of GMP as advocated by ISPE

One major source of risk to Quality (and Productivity) continues tobe the human being. Human errors (goof-ups and mix-ups)compromise Quality, place patients at avoidable risk, and also

adversely impact Productivity. Research world-wide spanning acrossdiverse industries report that 60% to 80% of product failures can directlybe attributed to human errors.

Why do humans make mistakes? Is it because they deliberately want to?Is it because the large majority of people are lazy? Or naturally inclinedto be disengaged? Or willfully avoid taking responsibility? Or drawsadistic pleasure in sabotaging the product or process? No. Nothing couldbe further from the truth. Most people want to be seen and work asprofessionals with integrity and capability, and enjoy making mistakes.

human errors


Studies indicate that such errors could be due to a wide variety of otherreasons, ranging from lack of or inadequate skill or competence for thejob; lack of or inadequate comprehension of the SOP; lack of orinadequate training; lack of or inadequate supervision; lack of orinadequate motivation or interest; fatigue; boredom; eye strain; illness;emotional strain; or, in the rarest of rare cases, through malicious intent.But, surprisingly, these are not the reasons cited most frequently. If youwere to prepare a Pareto Chart, you are likely to find that among themost common causes are “inadequate or lack of supervision” and“distraction” - shift-change; telephone call; meeting; visitors; non-availability of raw material in time; non-use-ability of raw material inhand; non-availability of equipment or instrument in time; non-availability of engineering support in time; non-availability of spares intime; non-availability of approval in time; non-availability of clarificationor direction in time - each of which could be studied, reviewed andremedied.

The Regulators have not specifically advocated such a review, but itwould be in your own interest to do so, and reap the rewards of highQuality together with high Productivity, lower costs and higher returns.

reasons for human error

To confirm the theories in circulation about reasons for human mistakes, Ihave been asking of the audience in all my lectures to narrate from theirown experience anecdotes of human errors and the reasons behind them. Iam placing before you a summary of my findings.

Figure 1: Causes for Human Errors and their respective frequency

31human errors as a source of risk to pharmaceutical quality

• Lack of or inadequate skill or knowledge

• Lack of or inadequate training

• Lack of or inadequate supervision

• Lack of or inadequate communication

• Lack of or inadequate staff: overworked, overlooked, oversight

• Physically, emotionally, or mentally stressed

• Disengaged –lacking commitment, no motivation, unwilling to work

• Continual irritants in the way of work

• Distractions

The single most prominent cause for errors, as anticipated, is Distraction,and I probed further to determine why one is distracted on the job:

1. Delay in approvals, instructions and/or clarifications2. Delay due to machinery malfunction3. Delay due to non-availability of tools or spare parts4. Delay due to non-availability of raw materials5. Phone calls6. Meetings7. Visitors8. Tea and Lunch Breaks

9. Shift-change

Figure 2: Errors due to distractions and their respective frequency


minimising risk of human error

From time immemorial, it has been a truth universally acknowledgedthat there is no substitute to “supervision” for effective control. A persondoes not become a good “supervisor” by mere virtue of being the seniormost in a group: there are several attributes one needs.

Some examples of “good” supervisors are Directors of films who keeprepeating “Cut!” every now and again, whenever they “sense” an out-of-turn movement; or Conductors at Orchestra Rehearsals who cry out“Stop!” whenever they “hear” a discordant note. Supervisors engage alltheir senses to “observe” the world around them, monitor, andimmediately “intervene” to prevent or correct an error, even as it isoccurring. The pharmaceutical manufacturing environment, sadly,impedes effective supervision.

As the word suggests, supervision is about “super” vision. You shouldbe able to first “see” to be able to “observe”. In other words, in orderthat you may “oversee”, the prime requirement is to be able to “see” inthe first place. Pharmaceutical layouts preclude such direct line of “sight”.In most other industries, a supervisor is “perched” in a cabin that issuspended from the ceiling, granting him a bird’s eye view of the shopfloor, on both sides. Automobile, aerospace, machine tools, semiconductorassembly are some examples of such an arrangement for supervision. A“suite within a suite” is more of a pharmaceutical phenomenon.Architects, who spend years in college to master the art of space sub-division, are politely instructed to adhere to the “approved” area layoutgiven to them by the User.

Figure 3: Supervisory attributes


Figure 4: Alternative area layouts that facilitate improvedsupervision

This issue is discussed at length by Wei Chak Joseph Lam of Singaporewho highlights this plight in his patent (US Patent No US 7,269,925 B2dated September 18, 2007), where he proposes various alternative layoutsthat can empower the supervisor to more effectively observe, monitorand intervene in time for better control over human beings while theyare at work.

Having said this, it must be emphasised that CGMP expects every personengaged in the manufacture, processing and holding of drug productsand drug substances to stay vigilant and alert at the workplace. Thelegal standard for responsibility and accountability is high, and peopleentering this field of endeavour should be aware of this special burden.

Note that in addition to proceeding against the drug, regulatoryaction may be taken against the person who is responsible for thefailure to comply. Responsibility for failure to comply would seemextensible vertically from senior management to line management,which did not supply adequate supervision or directions, throughquality assurance/ control and individual production people, whodid not follow directions, and horizontally to supplies of rawmaterials, whose products did not meet purported specifications,as well as to contract laboratories. Since criminal penalties (finesand/or prison sentences) are possible, these regulations impose a


standard of responsibility to have knowledge, to train subordinates,and to continually check to ensure compliance with directives.

The legal standard for responsibility for all those engaged in drugmanufacture is high. People entering this field of endeavor shouldbe aware of the special burden of complete accountability. Violationof the FFDC Act is handled under unique legal doctrine that doesnot require proof of criminal intent as a prerequisite for criminalculpability.

You cannot see your own face without a mirror: hence, you serve as themirror for those around you, detecting, preventing or correcting mistakesas they happen. You need not be the supervisor to protect the patientfrom potential harm!

remove bottle-necks

As we have seen earlier, a person who is focused on his work is completelyimmersed and engaged in what he is doing; and should he now getdistracted, he gets “dislodged” and loses concentration. Such an eventoften results in an error when he resumes. In cricket, every bowler fancieshis chances of getting a “set” batsman after a break, because of momentaryloss of concentration and “flow”: the same holds true in the work place.

The solution lies in identifying all such “speed-breakers” in his work, sothat his work continues uninterrupted. Delays in clarifications, instructions,approvals; non-availability of raw materials, tools, spares etc have thepotential to hurt the product and place the patient at undue risk.

Even more hazardous are interruptions caused by visitors, phone callsand breaks.

If you can identify these hazards, smoothen out the speed-breakers andbottle-necks, and put in place appropriate preventative measures, youwill be contributing immensely to Pharmaceutical Quality Managementin your plant to minimise risks of inadvertent human errors.

taking responsibility

Dr Edwards Deming, the renowned guru of Quality, Productivity andCompetitive Position, consistently encouraged Empowerment withResponsibility. Quality cannot be improved by adding more inspectors,but by addressing the inherent variability in a process, reducing layersof approval, and empowering the operator to take pride and responsibilityfor his work - a practice adopted by Toyota, among many others.


In contrast, in the pharmaceutical Industry, we have multiplicity of layers:written by, checked by, reviewed by, approved by, authorised by....

Since “responsibility” is “distributed”, no one is responsible, each, asrepeatedly pointed out by Dr Deming, citing examples from industry,assuming that someone else will detect any error, if there was one.

GMP recommends that a second person should witness/verify criticaloperations; but nowhere is it ever suggested that there ought to be more!If there are several stake-holders, the draft SOP may be circulated toeach, and their feed-backand inputs considered. But let one person write,and a second person, at the appropriate level, check, review, approveand authorise!

If the industry were to encourage employees to take responsibility andpride by empowering them to take timely decisions and interventionsmuch time could be saved, distractions avoided and productivityimproved.

For example, classify issues and related decision making as “A” (critical),“B” (major) or “C” (minor), and restructure the decision making processto levels appropriate to the issue at hand.

Improvement in Quality translates to improvement in Productivity, just asimprovement in Productivity translates to improvement in Quality. Qualityis about controlling variability; Productivity is about controlling wastages.

an overview of gmp

Documents

manufacturing organisation

drug product

drug substance

efficacyand quality

quality systems

countries cgmp

overviewthough material

toxicity studies