An Overview of GMP

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An introductory presentation that endeavours to capture and convey the spirit of Current Good Manufacturing Practices for drugs and devices, and place the humble operator and his CEO on the same page: What is GMP?What is GMP expected to do?Evolution of cGMPRegulators’ core valuesRegulators’ areas of concernRegulators’ rationaleHow much compliance is enough?Approaches to complianceWhy compliance initiatives fail?21st century approach to GMPWhy humans commit errors and how to minimise such occurrences?Does compliance create conflict or promote congruence between Product Quality and Productivity?

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current good manufacturing practices

an overview

c k moorthy

current good manufacturing practices

an overview

cgmp: an overview

c k moorthy

W

hy is GMP so crucial? Just reflect for a moment. When did you last pop a pill? Can you recall when you last administered any medicine to your near and dear ones? Did it occur to you at that time that the drug you were consuming or administering could be adulterated or misbranded? Did you consider having it tested to verify that the drug was indeed what the label claimed it was? No? Don’t worry. 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 sterilised infusions with their lives. Nearer home in Kolar, scores of hypertensive and hyperglycaemic patients died because their medicines were inadvertently interchanged at the manufacturer’s end during packaging and labeling. Little children on multivitamin courses developed severe

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reactions because of cross-contamination with a systemic allergen produced earlier in the same equipment train. Suffice it to say that the road 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 and blind trust in the pharmaceutical industry when you consumed your pill; but, disturbingly, they are not uncommon. Contrary to what you may have thought, drugs are not produced by infallible super humans in outer space. Veterans in the industry certainly recall lapses they themselves have witnessed over the years. Fortunately, most such blunders are discovered or detected in time before they leave the factory and reach the consumer. Current Good Manufacturing Practice (CGMP) endeavours to address these 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. It recognises that any manufacturing organisation has three distinctive aspects or elements: its resources (21CFR211 sub-sections B, C and D); its manufacturing process (21CFR211 sub-sections E, F and G); and its Controls (21CFR211 sub-sections H, I, J and K). Hence, CGMP may be defined as: “a quality system that seeks to demonstrate with documented evidence that the manufacturer has harnessed these three aspects or elements of his Organisation harmoniously to effectively deliver the drug or device that consistently, repeatedly and reproducibly meets or exceeds the quality, purity and other characteristics which it purports or is represented to possess.” In some countries CGMP is merely a guideline; but in most others it carries the weight of a law. Laws exist to safeguard some right or core value of a citizen, and CGMP is no different. core values WHO, European, Indian and other Regulatory Agencies advocate the following core values in a drug product or drug substance: Safety, Efficacy and Quality.

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Though Material Safety is already established through exhaustive and conclusive non-clinical safety and toxicity studies in GLP recognised test facilities; and Efficacy is proven beyond reasonable doubt in multi-phased clinical studies in GCP environments, the Regulators still seek reassurance at the drug or device manufacturer’s end that he is doing all that needs to be done to protect and promote such established safety and efficacy of the materials he handles from receipt, through processing till final delivery to the patient. The USFDA CGMP aspires to protect the patient with the same core values; but labeled differently: Safety : The product remains free of any unexpected side effects when used appropriately The product is exactly what the label and related material say it is; every material, component, significant piece of equipment and operation is labeled and documented so that lot histories can be accurately reconstructed from start to finish The concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or the potency, that is, the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard) Absence of substances that produce adverse effects on the product Fitness for intended use

Identity :

Strength :

Purity

:

Quality :

This is due to their recognition that Efficacy could be seriously compromised if there is any doubt about the Identity, Strength or Purity of 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 patient at risk. areas of concern Drug or device production has four, and just four, primary areas of concern that could potentially place a patient at risk: Contamination : Any substance or energy that adversely impacts upon drug/device performance

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Goof ups Mix ups Process inconsistency

: : :

Errors of omission and commission of human origin Special case of human error through gross negligence and carelessness A process that is unstable, unreliable and incapable

All regulating authorities around the globe share these core values and concerns. In fact, Inspectors, when faced with an unusual situation, are encouraged to apply the same risk analysis technique to assess compliance. The approaches they adopt for enforcement, however, can differ. For example, the US FDA makes its position clear with the following definitions 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 the body of man or other animals; and articles intended for use as a component of any articles specified above. * A drug is deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing or holding do not conform to or are not operated or administered in conformity with cGMP to assure that such drug meets the...quality and purity characteristics which it purports or is represented to possess. * Prosecution under “unique legal doctrine” that does not require proof of criminal intent as a pre-requisite for criminal culpability neither requires that actual harm from contamination of a drug product has to be proven for a charge that the product is adulterated, nor that each article in the batch be adulterated before the entire amount 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 minimise the 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 a product

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WHO has always stood firmly behind the need for Quality Systems to guarantee “Safety, Efficacy and Quality” of drug products. . The European Community, and our own Schedule M, echo these sentiments as well. Let us not forget that it was WHO that first launched the GMP initiative way back in 1967. The first World Health Organization (WHO) draft text on good manufacturing practices (GMP) was prepared at the request of the Twentieth World Health Assembly (resolution WHA20.34) in 1967 by a group of consultants. It was subsequently submitted to the Twentyfirst World Health Assembly under the title “Draft requirements for good manufacturing practice in the manufacture and quality control of drugs and pharmaceutical specialities” and was accepted. The revised text was discussed by the WHO Expert Committee on Specifications for Pharmaceutical Preparations in 1968 and published as an annex to its twenty-second report ( 1). The text was further reproduced (with some revisions) in 1971 in the Supplement to the second edition of The international pharmacopoeia. When the World Health Assembly recommended the first version of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce in resolution WHA22.50 (1969), it accepted 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 Davenport disaster; and US FDA’s CFR 210 and 211 were released only in 1978. Regulatory expectation levels and enforcement stringency are not uniform for all drug products or constituents. A general ranking is given here for formulations: O O 1 2 3 4 Research compounds, allergenics, toxics Sterile products and their processes Large Volume Parenterals (LVPs) 100ml -1000 ml Small Volume Parenterals (SVPs) 1 ml - 100 ml Opthalmics, other sterile products, medical devices Non-sterile products and their processes a Low-dose/high-potency tablets and capsules b Metered Dose Inhalers c Transdermal Delivery Systems (TDDs) d Drugs with stability problems e Other tablets and capsules f Oral liquids, topicals, and diagnostic aids

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For Bulk Pharmaceutical Chemicals, most Regulatory Agencies focus on only the Active Process Ingredient; only WHO has included Excipients under the GMP umbrella.

The full GMP Canvas EUGGMP WHO Schedule M

GMP expectations remain vague for some categories of products l i k e USFDA radiopharmaceuticals, where half-life constraints limit the application of GMP Figure 1: GMP as a Quality Philosophy vs
Guidelines & Regulations

Table 1: Application of GMP to API Manufacturing

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protocols in their entirety. While some guidance is available for biological products, it is woefully inadequate, and does not take into full account the very special and hazardous nature of these products. All the Regulatory Guidelines are not alike in their expectations. While there are large areas of common agreement, there are still differences in the fringes. As a consequence, any organisation that aspires to fully meet with just one such guideline may find itself short when measured against some other guideline. regulators’ rationale Why is there such variance in their respective expectations? To understand this, we must examine the philosophy that guides these agencies 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, which ease both compliance and enforcement burdens, with the need to encourage innovation and the development of improved manufacturing technologies * To provide manufacturers with the discretion on how to achieve the level of control necessary under GMP, recognising that in a few instances, more discretion from the agency is necessary because of the potential harm, the narrow range of acceptable means to accomplish a particular cGMP objective, or to provide a uniform standard to the industry * Recognising that the cGMP regulations would not achieve their statutorily mandated purposes if they were not periodically reassessed to identify and eliminate obsolete provisions or to modify provisions that no longer reflect the level of quality control that current technology dictates and the majority of manufacturers have adopted. * A GMP regulation is intended to be general enough to be suitable for essentially all drug products; flexible enough to allow the use of sound judgment and permit innovation; and explicit enough to provide a clear understanding of what is required. * A practice is adopted as GMP if it is feasible and valuable in contributing to assurance of consistency and homogeneity in product performance or value * To consider a practice GMP, it is not a pre-requisite that it be actually in use by a majority, or even a specific percentage of the Industry

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* A practice must be “current” and “good”. And to stay in compliance, practices must be continually updated. When and whether are matters of sound judgment influenced by the drug preparation under consideration. how much compliance is enough compliance? Adherence to the explicit regulations is a required minimum, but it is not adequate to ensure compliance. In other words, the Regulators view full compliance with their regulations as bare minimal expectation from any drug or device manufacturer, and encourage each to aspire to provide greater safety, efficacy and quality in the products offered to the patient. compliance reality check As the twentieth century drew to a close, there was, among pharmaceutical regulators in the developed world, specially in the US, a growing sense of unease that something was seriously amiss in the industry in terms of its quality, productivity and costs. While all other industries had forged ahead, the pharmaceutical industry was lagging behind in terms of technology and efficiency, trapped in some kind of time warp. In the words of Dr Ajaz S Hussain, USFDA, “The pharmaceutical industry has a little secret: even as it invents futuristic new drugs, its manufacturing techniques lay far behind those of potato chips and laundry-soap makers, who all have better control and better understanding of their manufacturing processes than do most pharmaceutical companies.” This sentiment was echoed by several others, including the Wall Street Journal, which carried a cover page article stating that the prevailing regulatory environment was forcing manufacturers to ship jobs overseas, since continuing in US was increasingly unviable. For example, manufacturing costs in pharmaceuticals is a startling US$ 90
Figure 2: The “crisis”

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billion, far in excess of its research investments. Once this recognition sunk in, the USFDA lost no time, spared no effort and left no stone unturned in its quest to remedy this sorry state of affairs. Expert Work Groups were set up, committees were put in place, suggestions were solicited from industry and academia – to identify what all 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 the first place. insecurity The USFDA’s position has always been: “A drug is deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing or holding do not conform to or are not operated or administered in conformity with CGMP to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. “Prosecution under “unique legal doctrine” that does not require proof of criminal intent as a pre-requisite for criminal culpability - neither requires that actual harm from contamination of a drug product has to be proven for a charge that the product is adulterated, nor that each article in the batch be adulterated before the entire amount is subject to condemnation or other action.” While it is fine as statements of “law”, it strains the relation between the Inspector and the Inspectee. Undercurrents of mutual suspicion and mistrust are inevitable, and the inspectee’s defences are forever on a high. The industry’s primary aim has been to be in a state of preparedness to 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

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to CGMP of today. The testing and documentation stayed on, around which a QA group was built, and somehow the “quality” part got lost; and QA became more based on documentation than on quality, and different 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 regarding documentation, and QA (wryly referred to in some circles as Department for “Quiet Adjustments”!) responded with its own corresponding set of corollaries and interpretations: Regulator’s Rule 1: QA’s Interpretation: If it is not written down, it didn’t happen. It’s just a rumour! If it is written down, Inspector will accept it as proof that it actually happened! So all you need to do is to just write it down! If it is not written down properly, it didn’t happen properly. You can never be certain as to what actually happened! If it is written down properly, Inspector will be sure as to what happened, and believe that it happened properly! So, see that you write it down properly! If the records are not correct, so is the product! If the records are correct, Inspector will presume that the product is also correct! So just ensure that your records are correct.

Regulator’s Rule 2:

QA’s Interpretation:

Regulator’s Rule 3: QA’s Interpretation:

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

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One manufacturer in Australia had perfected all this to a fine art! The deception went undetected until someone, hallucinating that his plane was on fire, frantically tried opening an aircraft door at 30,000’ to jump out, and triggered an investigation by TGA 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 showed you did what you said. Along came the era of validation when you were required to demonstrate with documented evidence as proof that your processes actually worked as intended. A process once validated was required to be maintained in a high state of control, and evidence of this must be maintained. For post-approval changes, the legal position is: The applicant must notify FDA of each manufacturing change in accordance with section 506A of the Federal Food, Drug, and Cosmetic Act and, when finalized 21 CFR 314.70 (CDER) and 514.8(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 license application(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 relate to the safety and effectiveness of the drug before distributing product made with the change (Section 506A of Act, Section 116 FDAMA). With the all-numbing fear of regulatory penal action hanging like the proverbial Damocles’ sword over the industry’s head, none would wish to attract 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!” the abiding rule. As a matter of fact, it is not uncommon in the industry to find the caveat: “Don’t use COMMONSENSE in place of SOP!” Where’s the room for good old commonsense in such a stifling environment anyway? confusing interpretations EUGGMP / WHO: “Alternative approaches are permitted if they are validated and provide equivalent levels of quality assurance”

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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 in each of the Annexes 1 to 17 inclusive in the Code, mean “must” and the activities, descriptions or specifications accompanied by the word “should” or “shall” are to be read as mandatory, unless the manufacturer is able to demonstrate that the activity, description or specification is inapplicable or can be replaced by an alternative which must be demonstrated to provide at least an equivalent level of quality assurance. USFDA on “Guidance”: Are manufacturers required to adhere to guidance? No. But if they are put out by the FDA, it is likely the investigator will find adherence to the guidance generally acceptable Significance of the phrase, “where appropriate”: 820.1(a)(3): In this regulation the term ‘‘where appropriate’’ is used several times. When a requirement is qualified by ‘‘where appropriate,’’ it is deemed to be ‘‘appropriate’’ unless the manufacturer can document justification otherwise. A requirement is ‘‘appropriate’’ if nonimplementation could reasonably be expected to result in the product not meeting its specified requirements or the manufacturer not being able to carry out any necessary corrective action. investigation findings regulatory woes O Regulatory uncertainties inhibit innovations or improvements O The rigidity and zeal of Regulatory Agencies to enforce, and the extreme anxiety in Industry to remain in compliance, has sadly combined 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 statistical methods inhibited industry’s application of Statistical Process Control methodologies industry woes Dr Janet Woodcock summarised the shortcomings in the industry succinctly: • • • • 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

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quality system CGMP as a Quality System, when compared with the Quality Systems employed 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 modern quality 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 review the Quality System No requirement for a Quality System – only Quality Unit functions are required No requirement for Continual improvement of the quality system No requirement for Continual improvement of process and product improvement Limited proactive approach (especially with preventive actions). While the industry did practice CAPA, it waited for things to go wrong before reacting, and seldom anticipated what may go wrong and use CAPA for taking proactive action for prevention.

quality O Materials not well characterised; process factors not well understood; cause of variability not well investigated; development trials treat process as uni-variate systems O Processes are held in a state of control, but little knowledge available about why or how they managed to attain that state O Enormous data collected, but little analysis, or efforts towards conversion 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 many definitions of the term as there were gurus preaching it. The pharmaceutical industry selected Juran’s: “Fitness for use”. The ICH expanded this to: “The suitability of either a drug substance or drug product for its intended use. This term includes such attributes as the identity,

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strength, and purity” (from ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances). Others who had opted for the Figure 3: What is Quality same definition soon discarded it as inadequate. For example, automobile transmission manufacturers in the US incurred three times as much by way of warranty costs as compared with their Japanese counterparts; and the reason turned out to be the wider variability in critical dimensions in the former’s process. The modern definition is that “Quality is inversely proportional to Variability”, and “Quality Improvement” is defined as “the reduction in the variability of processes and products” (or just “reduction of waste”). In other words to control Quality of a process, one must focus on identifying, controlling and reducing all those factors that contribute to its Variability. Hence, the revised definition of pharmaceutical “quality” states: Degree to which a set of inherent properties of a product, system or process fulfills requirements poor productivity Professor G K Raju , MIT, carried out an investigational survey and presented his findings to the FDA Science Board on some of the possible reasons for such high costs and wastes, and the crying need for fundamental technology and administrative
Figure 4: Production cycle

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changes: Archaic manufacturing technologies; poor production efficiencies and utilisation; large wastages; high costs of manufacture and compliance. Wastage of time and resources can be found from the time raw materials are ordered to the time the drug reaches the patient and the industry did not seem to care. In fact, the general perception in the industry is that Quality and Productivity cannot coexist one comes at the cost of the other. Professor Raju dwelt at length on the protracted production cycle times, and pointed out Figure 5: Production Delays the marked tendency to live with a “validated” process, rather than resolve a known process problem, producing almost as many lots with exceptions as those without. Often the time taken for QC testing and approval exceeded the manufacturing time several-fold. In a particular study, he observed that average cycle time was around 95 days, with a standard deviation of about the same duration, and this gets further impacted by over 50% in the event of an OOS result! With such low capacity utilisation, he stressed the need for fundamental changes in manufacturing and testing technologies. poor prioritisation While ABC classification was a common feature in other industries to help focus on the important few, rather than fritter away resources on the less significant many, there was no such comparable practice in the pharmaceutical industry. Risk Management was principally confined to Safety related issues, not applied to quality management or operations. For example, there was no distinction on issues, and all were being treated 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

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as “A” (critical), “B” (moderately critical) or “C” (minor). This was true for the Agencies as well, where the Regulator would treat all formulators alike in matters of oversight, without regard to how critical the formulation was for the patient, or its availability in the market or the manufacturer’s past track record with respect to GMP compliance or adverse events in the market. All this was only adding pressure on costs, 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 to be attained, both for the Industry as well as the Agency. O O O Barriers to continuous improvement to be reduced or removed 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 understood processes facilitating rational science, risk and business decisions A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight. Sustained and improved product quality and performance achieved and assured by design of effective and efficient manufacturing processes Specifications based on parameters that truly impact product quality - through mechanistic understanding of how formulation and process factors impact product performance Common understanding and language on risk. Both, industry and competent authorities focus on areas of greatest risk and understanding of residual risks An ability to effect continuous improvement and continuous “real time” assurance of quality

O

O

O

O

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

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As draft reports began trickling in, the USFDA realised the need to enlist the support of their counterparts in EU and Japan. Crack teams were dispatched to meet with them and discuss these “revolutionary” ideas. The mission was a total success. ICH Expert Working Groups were set to work on harnessing risk-based concepts and principles for Quality by Design (Q8), Quality Risk Management (Q9), and Life-cycle approaches to Pharmaceutical Quality Systems (Q10) with ASTM commissioned to develop standards for the emerging needs of advanced measurement 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 matter to the patient. In the words of the group that submitted its final report and Guidance on Process Analytical Technologies Framework: “At the end of the CGMP Initiative the pharmaceutical community has arrived at a cross-road; one path goes towards the desired state and the other maintains the current state. The path towards the desired state is unfamiliar to many while the current state provides the comfort of predictability. The Agency hopes the pharmaceutical community will choose to move towards the desired state.” current status ICH Q8, Q9 and Q10 have been adopted to change the mind-set and approach of the industry from a tick-box culture to one that is more science and

Figure 6: QRM driven process

Figure 7: New Quality System

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Figure 8: Management-centric Quality System

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

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Figure 10: Product Quality Life-cycle Implementation

risk-based; a Quality System has been proposed, similar to the one already in existence in the medical device industry, to have a management-led and management-driven Quality Culture that has at its core a “main quality system”, around which revolve satellite “sub-systems” to encourage different groups to take responsibility for quality in their respective turfs; ASTM E 2500 is in place since 2007 that rejected the sequential and ineffective DQ/ IQ/OQ/PQ approach to Qualification of buildings, facilities and equipment and replaced it with a more comprehensive science and risk-based Verification by Subject Matter Experts; and based on all these documents the new Process Validation Guide was released by USFDA in 2011, with EUGGMP in the process of aligning its Annexure 15, which has totally replaced all existing concepts of pharmaceutical validation and promotes Product Quality Life-cycle Implementation beginning with quality by design and 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 the industry, 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 embracing changes swiftly. It took the USFDA almost a decade to get their first

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major conviction. It took more than a decade, with much insistence and cajoling, to get pharmaceutical validation off the ground. It is over five years since QbD, QRM and ASTM E 2500 were released, but the changes mooted are yet to gain widespread acceptance. The focus of Quality Assurance continues to be on survival of Inspections and Audits; management-driven Quality System culture has not taken root; and the much expected change to science and risk based approaches to quality and productivity is yet to materialise. Yet I am optimistic. The industry is slow to move, but is not, and has never ever been, at standstill. It may be tardy, but it still is dynamic, not static. It may take five more years, or even longer, but eventually each of the manifold bold initiatives will bear fruit. And when that happens, the biggest 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? As already mentioned earlier, meeting one set of norms may leave you below the expectations of some other norm. Even if you take the sum total of all 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 practices find their way into the Guidelines, for various reasons. Now about cGMP compliance. Remember that “Compliance” means “obedience”; and “Regulatory Compliance” refers to initiatives calculated to 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 approached in one of two ways: from beneath, where norms appear as the ceiling; or from above, where norms represent the floor. The former approach is regulatory-driven compliance; the latter is culture- driven. Current and emerging regulatory expectations keeps practitioners of the former approach running to stay in the same place, while practitoners of the latter approach remain protected in a cocoon of comfort. All great “leaders”, organizations, individuals, regardless of the industry or profession they represent, have one link in common: they follow codes and disciplines that are largely self-imposed, and usually ahead of their times. This is what empowers and emboldens them to tread new grounds, blaze new trails and set new precedents. There is no discipline like selfdiscipline; no help like self-help.

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Regulatory Authority

Users & Vendors

Standards, Guidelines, GMP
Figure 11: The GMP cycle

Any practice, before it finds its way to a Regulation, is first adopted by a “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 any regulation. What you see as “regulation” is actually history of some achievement long past. The “leader” has since raised the bar even higher, nudged the frontiers even farther. Which explains why he is always in a zone of comfort when it comes to regulatory compliance. Compliance confers the following benefits, regardless of the approach taken: • 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” as they are, the approach towards compliance is predominantly “regulatory”: • • Understand and follow GMP regulations Validate manufacturing processes

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• • •

Implement effective master and batch production and control record 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 is purely to satisfy regulatory requirements, achieve satisfactory inspectional outcome and avoid regulatory citations. On the other hand, when you do things as a matter of Organisational culture or tradition, exceeding norms is not an unusual phenomenon. It is unconditional and the sole purpose is to achieve and sustain a high state of control. While those aspiring for regulatory compliance follow procedures laid down by others, the leaders design, implement and control their own procedures; validate and document critical processes and operations based on sound scientific principles and best technical practices The results are that the former group can at most achieve a state of GMP which is reactive and unstable; which can easily be upset by changes in regulations and guidelines; where employees must be frequently retrained on changed systems and procedures; which is influenced by latest inspectional trends and citations. Compliance here is a dependent variable: depends on compliance with current regulations. In contrast, wherever GMP is embraced as a gospel, there is automatic regulatory compliance, a high state of control, continuous improvement in operating and control systems, continual updating of skills and knowledge. It is proactive, independent of external trends and independent of cGMP The full GMP Canvas regulations and guidelines current or GMP as Culture emerging. Such organisations operate at a higher level than Sum total of all Regulatory cGMP, and well ahead Expectations because they operate in an environment with: Where you are today – a higher state of control designed into it – a science and technology base – an effective control & information system

Where you want to be tomorrow

Figure 12: GMP as culture

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“Observing Traffic Rules is a sign of civilisation” comments a hoarding in 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 before and after a meal; bathe at least once a day. Women are advised to stay isolated 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 than with many others’. Make GMP your culture, and you will never be out of compliance. make the drug as though it is for your own Regulating Agencies everywhere urge each person engaged in drug manufacture to act as they would if they knew that it was being made for one of their own family members. When your own child is in pain, and your physician is temporarily unavailable to visit you and gives you detailed instructions over phone to prepare a home remedy that would provide relief till he can come over, you never abdicate your responsibility by delegating to someone else, no matter how busy or pre-occupied you may be at the time. You drop everything you are doing, prepare the potions yourself and attend to your sick child. If you can show half as much dedication in your workplace as you do when tending to your child, 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 the market. Since they are not physically present at each manufacturer’s premises to oversee operations, they have entrusted this responsibility to the group within that Organisation called QC: to serve as a buffer between Vendors and Production and ensure that components allowed to enter the process bear the requisite quality characteristics and do not place the process at risk; and as a buffer between Production and the Patient, making sure that shoddy products never leave the door, so that no patient is ever put at risk. Such implicit trust is a huge responsibility, and calls for the highest level of integrity and professioanl excellence in the discharge of your duties.

Figure 13: Ten Principles of GMP as advocated by ISPE

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

human errors

O

ne major source of risk to Quality (and Productivity) continues to be 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 across diverse industries report that 60% to 80% of product failures can directly be 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 inclined to be disengaged? Or willfully avoid taking responsibility? Or draw sadistic pleasure in sabotaging the product or process? No. Nothing could be further from the truth. Most people want to be seen and work as professionals with integrity and capability, and enjoy making mistakes.

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current good manufacturing practices

Studies indicate that such errors could be due to a wide variety of other reasons, ranging from lack of or inadequate skill or competence for the job; lack of or inadequate comprehension of the SOP; lack of or inadequate training; lack of or inadequate supervision; lack of or inadequate 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 you were to prepare a Pareto Chart, you are likely to find that among the most common causes are “ inadequate or lack of supervision” and “distraction” - shift-change; telephone call; meeting; visitors; nonavailability of raw material in time; non-use-ability of raw material in hand; non-availability of equipment or instrument in time; nonavailability of engineering support in time; non-availability of spares in time; non-availability of approval in time; non-availability of clarification or direction in time - each of which could be studied, reviewed and remedied. The Regulators have not specifically advocated such a review, but it would be in your own interest to do so, and reap the rewards of high Quality together with high Productivity, lower costs and higher returns. reasons for human error To confirm the theories in circulation about reasons for human mistakes, I have been asking of the audience in all my lectures to narrate from their own experience anecdotes of human errors and the reasons behind them. I am placing before you a summary of my findings.

Figure 1: Causes for Human Errors and their respective frequency

human errors as a source of risk to pharmaceutical quality

31

• • • • • • • • •

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. 2. 3. 4. 5. 6. 7. 8. 9. Delay in approvals, instructions and/or clarifications Delay due to machinery malfunction Delay due to non-availability of tools or spare parts Delay due to non-availability of raw materials Phone calls Meetings Visitors Tea and Lunch Breaks Shift-change

Figure 2: Errors due to distractions and their respective frequency

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current good manufacturing practices

minimising risk of human error From time immemorial, it has been a truth universally acknowledged that there is no substitute to “supervision” for effective control. A person does not become a good “supervisor” by mere virtue of being the senior most in a group: there are several attributes one needs. Some examples of “good” supervisors are Directors of films who keep repeating “Cut!” every now and again, whenever they “sense” an outof-turn movement; or Conductors at Orchestra Rehearsals who cry out “Stop!” whenever they “hear” a discordant note. Supervisors engage all their senses to “observe” the world around them, monitor, and immediately “intervene” to prevent or correct an error, even as it is occurring. The pharmaceutical manufacturing environment, sadly, impedes effective supervision.

Figure 3: Supervisory attributes

As the word suggests, supervision is about “super” vision. You should be able to first “see” to be able to “observe”. In other words, in order that you may “oversee”, the prime requirement is to be able to “see” in the first place. Pharmaceutical layouts preclude such direct line of “sight”. In most other industries, a supervisor is “perched” in a cabin that is suspended from the ceiling, granting him a bird’s eye view of the shop floor, on both sides. Automobile, aerospace, machine tools, semiconductor assembly 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 subdivision, are politely instructed to adhere to the “approved” area layout given to them by the User.

human errors as a source of risk to pharmaceutical quality

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Figure 4: Alternative area layouts that facilitate improved supervision

This issue is discussed at length by Wei Chak Joseph Lam of Singapore who highlights this plight in his patent (US Patent No US 7,269,925 B2 dated September 18, 2007), where he proposes various alternative layouts that can empower the supervisor to more effectively observe, monitor and intervene in time for better control over human beings while they are at work. Having said this, it must be emphasised that CGMP expects every person engaged in the manufacture, processing and holding of drug products and drug substances to stay vigilant and alert at the workplace. The legal standard for responsibility and accountability is high, and people entering this field of endeavour should be aware of this special burden. Note that in addition to proceeding against the drug, regulatory action may be taken against the person who is responsible for the failure to comply. Responsibility for failure to comply would seem extensible vertically from senior management to line management, which did not supply adequate supervision or directions, through quality assurance/ control and individual production people, who did not follow directions, and horizontally to supplies of raw materials, whose products did not meet purported specifications, as well as to contract laboratories. Since criminal penalties (fines and/or prison sentences) are possible, these regulations impose a

34

current good manufacturing practices

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 drug manufacture is high. People entering this field of endeavor should be aware of the special burden of complete accountability. Violation of the FFDC Act is handled under unique legal doctrine that does not require proof of criminal intent as a prerequisite for criminal culpability. You cannot see your own face without a mirror: hence, you serve as the mirror for those around you, detecting, preventing or correcting mistakes as they happen. You need not be the supervisor to protect the patient from potential harm! remove bottle-necks As we have seen earlier, a person who is focused on his work is completely immersed and engaged in what he is doing; and should he now get distracted, he gets “dislodged” and loses concentration. Such an event often results in an error when he resumes. In cricket, every bowler fancies his chances of getting a “set” batsman after a break, because of momentary loss of concentration and “flow”: the same holds true in the work place. The solution lies in identifying all such “speed-breakers” in his work, so that his work continues uninterrupted. Delays in clarifications, instructions, approvals; non-availability of raw materials, tools, spares etc have the potential to hurt the product and place the patient at undue risk. Even more hazardous are interruptions caused by visitors, phone calls and breaks. If you can identify these hazards, smoothen out the speed-breakers and bottle-necks, and put in place appropriate preventative measures, you will be contributing immensely to Pharmaceutical Quality Management in your plant to minimise risks of inadvertent human errors. taking responsibility Dr Edwards Deming, the renowned guru of Quality, Productivity and Competitive Position , consistently encouraged Empowerment with Responsibility. Quality cannot be improved by adding more inspectors, but by addressing the inherent variability in a process, reducing layers of approval, and empowering the operator to take pride and responsibility for his work - a practice adopted by Toyota, among many others.

human errors as a source of risk to pharmaceutical quality

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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, as repeatedly 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 critical operations; but nowhere is it ever suggested that there ought to be more! If there are several stake-holders, the draft SOP may be circulated to each, and their feed-backand inputs considered. But let one person write, and a second person, at the appropriate level, check, review, approve and authorise! If the industry were to encourage employees to take responsibility and pride by empowering them to take timely decisions and interventions much time could be saved, distractions avoided and productivity improved. For example, classify issues and related decision making as “A” (critical), “B” (major) or “C” (minor), and restructure the decision making process to levels appropriate to the issue at hand. Improvement in Quality translates to improvement in Productivity, just as improvement in Productivity translates to improvement in Quality. Quality is about controlling variability; Productivity is about controlling wastages.

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