AAPharmaSyn, Author at AApharmaSyn

October 3, 2022October 3, 2022

Proteolysis-Targeting Chimeras (PROTACs) in Cancer Therapy

Proteolysis targeting chimeric (PROTAC) technology is a recently discovered technique that has profound efficacy in cancer. This approach was first established in 2001. It is based on a ubiquitin-proteasome system that works to degrade target proteins via ubiquitination, thus suppressing the growth of tumors. Many kinds of research and clinical trials have been performed recently to determine the effect and feasibility of PROTAC technology in degrading endogenous proteins that have shown promising results. One of the most promising and encouraging results was found in oral PROTAC therapy in breast cancer and prostate cancer treatment. (1)

Mechanism of Action of PROTAC:

Different physiological and pathophysiological mechanisms work in our body for the degradation of proteins, including cell cycle control, gene transcription, apoptosis, etc. Among all these systems, PROTAC technology uses a ubiquitin-proteasome system (UPS) for the targeted degradation of protein in different cancerous and tumor cells. UPS depends on ATP for its activity and has two ordered steps, including:

Polyubiquitination of the target protein
Proteolysis of polyubiquitin by 26S proteolytic enzyme complex

PROTAC molecules attach E3 ligases to a target protein that initiate the degradation process by ubiquitination of target proteins by E3 ligases. Proteasome (26S) then degrades this ubiquitinated protein, and the activity of PROTACs is not dependent upon the kinase activity of target proteins. (2)

Effects of PROTAC During the Course of Cancer Causation:

Initiation and progression of cancer is a complex process, including different pathophysiological changes in the cells, including proliferative signaling, inhibiting growth suppression, induction of angiogenesis, countering cell death, and activation and local invasion and distant metastasis. Evidence-based research and clinical trials have explained the crucial role of overactivated and overexpressed proteins in the initiation and progression of cancer. These proteins are the focus of most of the therapeutic approaches used for the treatment and abolishment of cancer and different associated factors. (3) Here, we will précis about the PROTAC approach in cancer therapy.

Cancer Cell Proliferation:

PROTAC technology targets proteins that are hyperactivated or mutated and result in cell cycle progression that favors cancer cell proliferation. One main pathway of cell cycle regulation that is hyperactivated in proliferating cancer cells is the RAS-RAF-MEK-ERK pathway. Proteins act as inhibitors or accelerators for regulating the cell cycle by controlling CDK expressions. CDKs and their chaperones release transcription factor E2F by phosphorylation of retinoblastoma protein resulting in DNA replication. Growth signaling and progression also depend upon the RAS-RAF-MEK-ERK pathway, which plays a key role. Until now, PROTACs have been developed that target oncogenic proteins including BRD4, EGFR, CDK4/6, AURORA-A, CDK2/5, MEK1/2, HER, etc. (4)

Cancer Apoptosis:

Apoptosis is the programmed death of the cells that helps to maintain tissue hemostasis during DNA damage, immune surveillance, and cellular stress. In cancerous cells, proteins favoring cell death are downregulated, and those inducing cell survival are upregulated. It increases cell survival, resistance to endogenous and exogenous apoptotic factors, and cancer causation and recurrence. PROTACs target proteins that regulate apoptosis, thus improving the effects of anticancer factors and increasing the programmed death of the cells. Downregulation of antiapoptotic proteins, including Bcl-2, Bcl-xL, Bcl-6, and Mcl-1, and upregulation of proapoptotic proteins, including Bax and Puma, by PROTACs make them a better therapeutic choice for the treatment of different types of cancers. (5)

Cancer Angiogenesis:

Tumor cells require neurovascular supplies to get nutrients and excrete waste products essential for their growth and proliferation. Angiogenesis depends upon various factors, including VEGF (a principal factor), whose expressions are activated by hypoxia resulting in the induction of angiogenesis. PROTAC technology can target these growth factors that can result in the suppression of angiogenesis and proliferation of cancer cells. Growth factors that are the targets of PROTACs in the inhibition of angiogenesis include VEGFR2, PI3K, CBP/p300, etc. (6)

Cancer Immunity and Inflammation:

Tumor cells involve activated signaling of different regulatory cells, including T-cell receptor (TCR) and B-cell receptor (BCR), that cause reprogramming of cancerous microenvironment leading to immune evasion and inflammation. These processes are essential for tumor cell survival. Immunotherapies have significant roles in enabling immune-meditated clearance of cancer cells. However, some patients have resistance to these therapies. PROTACs can target the proteins that carry out different pathways, such as TCR, BCR, and JAK-STAT pathways. They have evidence-based activity against BTK, PD-L1, STAT3, ITK, JAK, etc., which are essential in carrying out TCR, BCR, and JAK-STAT pathways. (4)

Cancer Metastasis:

Cancerous cells can successfully disseminate and travel via blood or lymphatic circulation and colonize distant organs away from their primary site of occurrence. This process is called metastasis which is responsible for approximately 90% of cell deaths worldwide. Metastasis requires a key step called Epithelial-to-mesenchymal transition, which is dependent upon different cellular signaling pathways, including Integrin/FAK/PI3K/AKT axis. PROTACs have been developed in past few years to target proteins related to Epithelial-to-mesenchymal transition. The key pathways involved in increased expression of Epithelial-to-mesenchymal transition include Integrin/FAK/PI3K/AKT, Wnt/β-catenin, and TGF-β/SMAD. PROTACs can target proteins involved in the regulation of these pathways, such as FAK, Smad3, p38, IGF-IR, TCF, etc. (3)

Conclusion:

In the bottom line, PROTAC technology has extensively progressed from its start in 2001, with significant efficacy in improving cancer treatments. However, there is still a need to have more clinical trials and evidence-based research on its efficacy. The effects of PROTACs in controlling cancer progression and its counterattacking mechanisms during different steps of cancer cell growth, proliferation, and spread have been studied. However, developing different types of PROTACs with specific advantages and overcoming disadvantages and therapeutic efficacy and safety need more study.

References:

Xie H, Liu J, Alem Glison DM, Fleming JB. The clinical advances of proteolysis targeting chimeras in oncology. Explor Target Antitumor Ther. 2021;2(6):511–21.
Qi SM, Dong J, Xu ZY, Cheng XD, Zhang WD, Qin JJ. PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy. Front Pharmacol. 2021 May 7;12.
Wang C, Zhang Y, Zhang T, Shi L, Geng Z, Xing D. Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges. J Enzyme Inhib Med Chem. 2022 Dec;37(1):1667–93.
Li X, Song Y. Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy. J Hematol Oncol. 2020;13(1):50.
Li X, Pu W, Zheng Q, Ai M, Chen S, Peng Y. Proteolysis-targeting chimeras (PROTACs) in cancer therapy. Mol Cancer. 2022;21(1):99.
Ocaña A, Pandiella A. Proteolysis targeting chimeras (PROTACs) in cancer therapy. J Exp Clin Cancer Res. 2020 Sep 15;39(1):189.

February 22, 2021April 10, 2021

The Importance of Synthetic Organic Chemistry in Drug Discovery

In recent years, many pharmaceutical companies have chosen to reduce their R&D investment in chemistry, viewing synthetic chemistry more as a mature technology and less as a driver of innovation in drug discovery. Moreover, there seems to be an underlying current of thought that hard work and determination could offset the elegance of design and creative ideation. We coldheartedly believe that excellence and innovation in synthetic chemistry will continue to be critical to success in all phases of drug discovery and will not be commoditized at least in the foreseeable future.

Over the past century, innovations in synthetic methods have changed the way scientists think about designing and building molecules, enabling access to more expansive chemical space and to molecules possessing the essential biological activity needed in future investigational drugs discovery. Innovation in synthetic chemistry provides opportunity to gain more rapid access to biologically active, complex molecular structures in a cost-effective manner that can change the practice of medicine.

An outstanding example of the transformative power of synthetic chemistry in drug discovery is the application of carbenoid N-H insertion chemistry to the synthesis of b-lactam antibiotics. The application of ring closing metathesis chemistry has been transformative in the synthesis of many HCV NS3/4a protease inhibitors of varying ring sizes and complexity, including six approved drugs: simeprevir, paritaprevir, vaniprevir, grazoprevir, voxilaprevir, and glecaprevir. Ring closing metathesis chemistry enabled the discovery of these and related macrocycles, allowing rapid assembly of complex bioactive molecules and broad exploration of SAR to address a range of properties.

Owing to the diverse biological activity of nitrogen-containing compounds, the discovery of Pd-catalyzed and Cu-catalyzed cross-coupling reactions of amines and aryl halides to form C-N bonds resulted in the rapid implementation of these synthetic methods in the pharmaceutical industry.

The ability of the pharmaceutical industry to discover molecules to treat unmet medical needs and deliver them to patients efficiently in the face of an increasingly challenging regulatory landscape is dependent on continued invention of transformative, synthetic methodologies. To this end, investment in research directed toward synthetic methods innovation and developing new technologies to accelerate methods discovery is essential.

Over the past 20 years, several scientists have been recognized with the Nobel Prize for the invention of synthetic methodologies that have changed the way chemists design and build molecules. Each of these privileged methods — asymmetric hydrogenation, asymmetric epoxidation, olefin metathesis, and Pd-catalyzed cross-couplings — have broadly influenced the entire field of synthetic chemistry, but they have also enabled new directions in medicinal chemistry research. Of particular interest are new synthetic methods that enable medicinal chemists to control reactivity in complex, drug-like molecules, access nonobvious vectors for SAR development, and rapidly access new chemical space or unique bond formations.

As the development of transition metal–catalyzed processes has advanced, application of cutting edge methods to the predictable activation of C-H bonds for functionalization of complex lead structures can enable novel vector elaborations, changing the way analogs are prepared. In particular, late-stage selective fluorination and trifluoromethylation of C-H bonds in an efficient, high-yielding, and predictable fashion permits the modification of lead compounds to give analogs that potentially possess greater target affinity and metabolic stability without resorting to de novo synthesis.

Adoption of photoredox catalysis in the pharmaceutical industry has been rapid, owing to the practicality of the process, the tolerance to functional groups in drug-like candidates, and the activation of nonconventional bonds in drug like molecules. Application of photoredox catalysis to the Minisci reaction was reported, enabling the facile and selective introduction of small alkyl groups into a variety of biologically active heterocycles such as camptothecin.

Even more remarkable transformations are being reported via synergistic catalysis, where both the photocatalyst and a co-catalyst are responsible for distinct steps in a mechanistic pathway that is only accessible with both catalysts present. For example, the combination of single-electron transfer–based decarboxylation with nickel-activated electrophiles has provided a general method for the cross-coupling of sp²-sp³ and sp³-sp³ bonds. This method establishes a new way of thinking about the carboxylic acid functional group as a masked cross-coupling precursor, expanding the synthetic opportunities for a functional group that is ubiquitous in chemical feedstocks. Furthermore, leveraging synergistic catalysis with photoredox has resulted in the discovery of milder conditions for C-O and C-N cross couplings, allowing application of these methods to more pharmaceutically relevant substrates.

Despite the many advances described above, the pace and breadth of molecule design is still constrained because of unsolved problems in synthetic chemistry. Many opportunities still remain to advance the field, such that synthetic chemistry will never constrain compound design or program pace and should actually inspire access to uncharted chemical space in the pharmaceutical industry.

Key unsolved problems in synthetic chemistry included selective saturation and functionalization of heteroaromatics, concise synthesis of highly functionalized, constrained bicyclic amines, and C-H functionalization for the synthesis of a,a,a-trisubstituted amines. Other areas, such as selective functionalization of biomolecules and synthesis of noncanonical nucleosides, are emerging areas of high potential impact.

Synthetic chemistry has historically been a powerful force in the discovery of new medicines and is now poised to have an even greater impact to accelerate the pace of drug discovery and expand the reach of synthetic chemistry beyond the traditional boundaries of small-molecule synthesis. New methods of synthesis can greatly expand the rate of molecule generation while also providing opportunities to routinely synthesize complex molecules in the course of drug discovery.

Continued investment in synthetic chemistry and chemical technologies has the promise to advance the field closer to a state where exploration of chemical space is unconstrained by synthetic complexity and is only limited by the imagination of the chemist. Advancements in synthetic chemistry are certain to remain highly relevant to the mission of inventing new medicines to improve the lives of patients worldwide.

February 11, 2021February 11, 2021

Preclinical Services

Most Preclinical CROs provide studies that aim at providing information about safety and efficacy of a drug candidate before testing it in humans. Furthermore, they can provide evidence for the compound’s biological effect and usually include both in vitro and in vivo studies. Preclinical studies have to comply with the guidelines dictated by Good Laboratory Practice to ensure reliable results and are required by authorities such as the FDA before filing for approval as IND. Insights into the compound’s dosing and toxicity levels are essential to determine whether it is justified and reasonably safe to proceed with clinical studies and are provided by studies on pharmacokinetics, pharmacodynamics, and toxicology. (Honek, 2017)

Pharmocodynamics (what does the drug do to the body?). Pharmacodynamics describes the relationship between the concentration of a drug in the body and its biological effect (dose response). This includes addressing the question, how potent and efficacious the drug is with regard to its desired pharmacological effect, including safety aspects and AEs (adverse events). Thus, pharmacodynamics establishes the therapeutic index of a drug, describing the ratio of the dose causing toxicity and the dose eliciting a therapeutic effect. Ideally, the therapeutic index is large to indicate a wide therapeutic window.

Pharmacokinetics (what does the body do to the drug?). The effect of a drug is determined by the amount of active drug present in the body particularly at the target site. This, in turn, depends on absorption, distribution, metabolism, and excretion (ADME) of the compound. Pharmacokinetics describes changes in plasma concentrations over time as a consequence of ADME. ADME profiling is critical for establishing dose range and administration schedule for subsequent phases of the clinical trial.

Most drugs are administered orally and need to be absorbed in the gastrointestinal tract to enter the bloodstream, allowing them to be transported to their site of action. On its way to the target site, the drug reaches the liver, where first-pass metabolism takes place. Consequently, the drug concentration – and thus its bioavailability – is reduced before entering systemic circulation. Intravenous drug administration bypasses the first-pass effect, resulting in greater bioavailability. Once in the circulation, the drug is transported to different tissues. Distribution of the compound throughout the body is determined by (i) the drug’s affinity for plasma proteins, (ii) the drug’s molecular properties and polarity, and (iii) tissue vascularisation. After entering the body, drugs are metabolised to facilitate elimination. Metabolism refers to the chemical alteration of the parental drug into pharmacologically active or inert metabolites. To ensure adequate long term dosing and appropriate steady-state concentrations of the drug, it is critical to obtain information on drug elimination from the body (clearance). Clearance is mainly achieved via the renal and hepatic routes; however, pulmonary clearance plays a major role for volatile drugs such as anaesthetics. Concomitant disease, lifestyle factors, and patient’s age can affect clearance and these are frequently studied in later stages of the clinical trial. When the rate of clearance equals the rate of absorption, a so-called steady state is reached. Typically, maintaining a stable steady state level is desirable and can be achieved through repeated dosing. Eventually, the drug and its metabolites are excreted from the body mainly through urine or feces.

Toxicology (it is efficacious, but is it safe?). To determine whether a drug is safe for testing in human subjects, preclinical toxicology studies are performed to identify the treatment regimen associated with the least degree of toxicity and thus determine a suitable and safe starting dose for clinical trials. Additionally, they can be used to establish biomarkers for monitoring potential AEs later. Starting with single-dose studies to identify organs that might be subject to drug toxicity, preclinical in vivo studies continue with repeated-dose approaches. The treatment regimen ideally mimics the intended clinical

design with respect to treatment duration, schedule, and route of administration. Other studies evaluate carcinogenicity, genotoxicity, and reproductive toxicity. While the drug’s genotoxic effect is usually studied based on its potential to induce mutations in yeast-based in vitro systems, carcinogenicity and reproductive toxicity studies typically involve rats. As the tumorigenic effect of a drug may only become evident after prolonged exposure, carcinogenicity studies comprise continuous drug administration for a minimum of six months.

In vitro models (studying the drug in a petri dish). In vitro studies are a relatively fast, simple, and cost-efficient way of preclinical testing. Those studies utilize cell, tissue, and organ cultures, or focus on particular cell components such as proteins or other biological macromolecules. In vitro studies permit tight control and monitoring of experimental settings and often provide mechanistic evidence for the investigational compound’s mode of action. While having the potential to provide mechanistic insights, in vitro models are constrained by the fact that isolated cells may not behave in a petri dish as they would within the body where they partake in crosstalk and interaction with millions of other cells. Consequently, more sophisticated preclinical models are required to establish the investigational compound’s safety profile before transitioning to a clinical setting.

In vivo models (is the mouse the best experimental animal?). In vivo studies consider the complete organism based on various animal models. The choice of appropriate animal models depends on myriad criteria and requires understanding of species-specific physiology and similarity with regard to the target organ, metabolic pathways as well as financial, regulatory, and ethical considerations. Typically, in vivo studies are performed in a rodent (e.g, mouse, guinea pig, hamster) and non-rodent model to comply with FDA requirements. Mice, rats, and dogs are among the most frequently used animal models while testing in primates (e.g., monkeys, apes, etc.) is performed occasionally and typically for larger molecules.

February 11, 2021February 11, 2021

Drug Discovery and Development Process

Drug Development | AAPharmaSyn | Drug Discovery & Development

Discovering and developing a new therapeutic can take 10-15 years, on average, with costs often exceeding $1 billion. For every 10,000-15,000 compounds initially evaluated, only five advance to human testing, and only one is ultimately approved for commercialization. The increasingly complex drug development process requires therapeutic expertise, advanced technological capabilities, and familiarity with the increasingly complex regulatory process. As the time and resources needed to develop new compounds rises, jobs that used to be performed by biopharmaceuticals in-house laboratories are increasingly being outsourced to CROs that can complete them 30% more quickly. With the enormous costs at hand and risks involved throughout the process, biopharmaceutical companies, understandably, seek outsourcing partners that possess the necessary expertise and scale to maximize the chances of ultimate approval, navigate the regulatory hurdles, compress the development timeline where possible, and produce a quality end-product with a successful clinical trial. This generally positions larger CROs more favorably than smaller providers, given their broader therapeutic expertise and global footprints, regulatory expertise in numerous geographies, and advanced technological capabilities. In addition to discovering and developing new compounds, biopharmaceuticals also often task CROs with improving existing drugs. The advantages of CROs in this process can save biopharmaceutical companies three to five months’ time and generate $120-150 million more revenue. (Wilson, Willoughby, & Wallach, 2016)

Pre-Discovery. At this early stage, researchers attempt to understand the causes of a disease at a molecular level and identify diseases that new therapeutics could potentially target. Recent advances in molecular medicine and powerful technological tools that enhance computational capacity greatly improve the efficiency of this process and enable researchers to better understand human diseases at the molecular level. Biopharmaceutical companies often perform basic research independently, as well as in partnership with external researchers and academic institutions.

Drug Discovery. The ultimate goal of the drug discovery phase is to find a promising molecule, or lead compound, that has the potential to become a new medicine. Researchers assess the underlying disease pathway and identify potential target compounds, narrowing the field of compounds to one lead compound that shows potential to influence the target. Researchers can create a molecule from living or synthetic materials and using high-throughput screening techniques, select a few promising molecules from an initial pool of as many as 10,000-15,000 compounds. Researchers can also identify compounds found in nature or genetically engineer living systems to produce disease-fighting molecules.

Preclinical Research (Pre-human). Relevant compounds are tested in-vitro (test tubes) and in-vivo (animals) over a wide range of doses to establish relative toxicity of the compound and detect any potential adverse reactions to the therapeutic. If results of preclinical research indicate that the compound is safe and potentially effective, the sponsor submits initial study results to the FDA along with a complete Investigational New Drug Application (IND). An IND includes, among other things, preclinical study data, Chemistry, Manufacturing and Controls (CMC) information, and an investigational plan for clinical trials, and it must become effective before proceeding to clinical trials. An IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns relating to proposed clinical trials within the 30-day time period, in which case the FDA’s concerns must be addressed before clinical trials can commence. Before clinical trials can begin at a study site, the site’s Institutional Review Board (IRB), an independent expert body charged with protecting patient safety and privacy, must give their approval, separately from the IND submission.

Clinical Trials. Of the 250 compounds that advance to preclinical testing for a particular project, only five, on average, progress to clinical (human) testing. Clinical trials are completed to determine the safety and efficacy of a drug. Clinical trials can last six to seven years and comprise Phases I-III, with Phase IV or post-commercial marketing studies often required by the FDA as well. These trials often involve the use of placebos, where some subjects receive the new drug candidate and others receive an alternative treatment (placebo), with randomization (patients are randomly selected to receive either the actual compound or a placebo) and double-blinded protocols (where neither the researcher or subject know which patients are given the actual drug candidate or a placebo) in order to minimize biases. We describe the primary clinical testing phases in more detail below.

Phase I: During the earliest phase of clinical trials, testing is focused on basic safety and pharmacology, typically completed using 20 to 100 healthy human volunteers, though sometimes stable patients that exhibit the targeted disease are also included. Inpatient studies often take place at specialized research centers known as a Clinical Pharmacology or Clinical Research Units (CPU or CRU). These studies evaluate human metabolic and pharmacologic reactions to the compounds, the duration of effectiveness and activity, how it is affected by other drugs, how it is tolerated and absorbed, and how it is broken down and excreted from the body. Multiple dosage ranges and methods are analyzed, with side effects also carefully monitored. Once these studies are completed with satisfactory results, testing of efficacy is commenced.

Phase II: Sometimes referred to as proof-of-concept studies (POC), this stage of clinical testing focuses on basic efficacy, with dose-range testing completed in 100 to 500 patients afflicted with the targeted disease or condition. During this stage, though the primary focus is efficacy evaluation, further safety testing is also completed, along with determination of optimal dosage levels, dosage schedules, and administration routes. If Phase II studies yield satisfactory results, Phase III can commence, provided that no hold is placed on further studies by the FDA. It is during Phase II that the majority of drugs under development fail.

Phase III: Trials at this stage are completed at a larger scale, across multiple testing centers, in populations of 1,000-5,000 patients afflicted by the target disease. During this stage, advanced efficacy and safety testing is completed in order to provide enough data for valid statistical conclusions required by the FDA and other relevant regulatory bodies, as well as to provide an adequate basis for product labeling, optimal dosage, formulations, and administration methods. This stage is typically the longest and most expensive phase, and two successful Phase III trials demonstrating a drug’s safety and efficacy are often required to obtain FDA approval. Roughly 50% of drugs that enter Phase III testing fail. Once Phase III test results are approved by the FDA, the drug sponsor can submit a new drug application (NDA) or biologics license application (BLA), depending on the nature of the compound and disease.

FDA Review. After determining that the results of the clinical trials indicate that the compound is safe and effective, the sponsor submits an NDA or BLA to the FDA requesting approval to market the drug. Included with the NDA or BLA submission are the comprehensive testing results and supporting data and analysis from both preclinical and clinical testing, along with proposals for manufacturing plans and labeling. These applications are often over 100,000 pages. There are strict protocols that govern the submission process, and failure to abide by them can be grounds for rejection.

Post-Marketing Surveillance and Phase IV Studies. Once a drug is approved by the FDA, the agency often requires the sponsor to collect and periodically report additional safety and efficacy data to the FDA. At times, this can occur throughout the entire marketed lifespan of the product. If the product is marketed internationally, surveillance reports must include data from all countries in which the drug is sold. The FDA may require additional studies (Phase IV) even following approval, to test the compound for other potential indications, or new dosage formulations. The FDA and other regulatory agencies may also require license holders to prepare risk management plans that assess areas of product risk and plans to actively manage such risks.

September 29, 2020April 10, 2021

Self-Deception

Skepticism is the cornerstone of science. Much progress has been achieved by questioning established status quo and gathering social support toward finding answers to naturally occurring phenomena. It is hard to envision scientific progress without challenging status quo and finding empirical evidence to dispute established beliefs in favor of more accurate representation of reality. Furthermore, human ability to symbolically represent and challenge ideas affords tremendous opportunity to advance understanding of natural phenomena. It is perhaps most pronounced within the confines of theoretical physics and mathematics where theory most often precedes experimental observation.

Despite being powerful tool when applied judiciously, untethered from reason, skepticism takes form of self-deception. One cannot deceive oneself into believing something while simultaneously knowing it to be false. Hence, literal self-deception cannot exist. In genuine self-deception, people avoid doing things that they have an inkling might reveal what they do not want to know. However, suspecting something is not the same is not knowing it to be true. As long as one does not find out the truth, what one believes is not known to be false. Keeping oneself willfully uninformed about an unwanted truth in the main vehicle of genuine self-deception.

Within physical and life sciences experiments are nuanced and the number of explanatory parameters is large. As such it is quite easy to cast explanatory powers onto obscure experimental conditions employing confounded logic and elaborate causative schemes. Nonetheless scientific method is self-correcting and it is a rare, albeit still observable phenomenon when much effort must be placed into refuting indefensible propositions e.g. flat earth theory, supernatural powers, etc.

However, within the fabric of human interaction self-deception is highly pronounced. By not pursuing courses of action that would reveal the actual state of affairs, individuals keep the knowable unknown. For example, within the contract research services sector it is rare when clients and service providers are completely transparent about the state of business relationship. Service providers are often reluctant to initiate meaningful performance conversation for the fear that they may have to provide additional services at no extra cost or worse they open pandoras box and then have to deal with whatever comes out of it. Instead the common course of actions is to presume all is well and then act surprised when tensions reach inflection point.

From the client standpoint it is customary to treat service providers respectfully but highly tactically. Given that within lower mid-market sector, service providers are in general much smaller than their client base and contribute small but very important inputs to the overall success of client objectives, external partner management practices either do not exist, are not actively implemented or implemented in a haphazard manner. Generally unwritten and unsaid justification for this approach is that the return on meaningful engagement with a small CRO is not justified and therefore the effort is not expended. More strikingly is that partner management methodology is rarely discussed at the client and when discussions do take place the conversations usually center around specific examples from which omnibus extrapolations are made without much concern to logical coherence.

Despite being widespread and systemic actors’ self-deception as it relates to service provider-sponsor interactions within the confines of the CRO industry does not cause much concern and is generally not given much attention. We recognize our limited knowledge of the clients we engage with and appreciate the number and complexity of tasks they have to deal with. To that end our approach is to strive toward complete transparency and enable our partners to make the best decisions that yield the most value to them. Whenever we identify and validate an issue that affects our performance we do not hold back and are forthcoming so that corrective measures are taken expediently. We firmly believe and can empirically support our assertions that deliberate effort to stay uninformed will adversely impact our ability to generate value for our clients and is both ethically and morally unacceptable.

September 29, 2020April 10, 2021

Scientific Mindset

It is not unusual to observe a large number of trends affecting everyday life come in and out of vogue. Fashion is a prime example where designs pop in an out of existence and only those that demonstrate a unique functional and aesthetic value are relegated to the iconic status. Especially so in physics, the progress achieved in the last century has been life-changing to billions of people. It is telling that all new discoveries were underpinned by inquisitive mindset and methodical approach toward elucidating the nature of reality with luck sprinkled in for good measure. Herein we explore what it means to practice scientific mindset.

In our own work we are frequently faced with a problem that is difficult to conceptualize and establish a hierarchy of contributing determinants. Many times, there is a significant degree of covariation and high sensitivity to initial conditions such that applying regression analytics is either impractical or simply not possible due to the small sample size. As such synthetic chemistry practitioners are left with the dilemma on how to improve predictive algorithm without trying to “boil the ocean”.

Broadly speaking synthetic chemists can be divided into two camps. In once camp one finds folks who demonstrate action bias and combinatorial mindset. They go and try the reactions because they may have a chance of yielding desired outcome. Literature precedence is incorporated albeit in a superficial capacity and most effort is expended toward conducting the experiments. “Failed” experiments are quickly discarded unless they yield obvious methodological flaws and little time is spent triangulating hypothesis, overall strategy and empirical data.

The second camp contains individuals who are prone to overanalyze and overextrapolate information gathered from preliminary diligence. Much discussion ensues about which experiments are to be conducted and why. Ubiquitously, personal bias is injected into discussion as a justification for a specific argument. Not surprisingly much time and emotive energy can be spent without having anything to show for it. Moreover, once the experiment is actually performed the results are analyzed to extreme degree frequently generating far fetched conclusions on the basis of confounded assumptions.

Through trial and error we came to appreciate the utility of context based approach that generates empirical results without sacrificing strategic rigor. In our view it is critically important to establish definitiveness of purpose and not do anything unless there is sound and rational justification for taking action or not. That is we happily engage in “trial and error” type investigations when the project is characterized by unknown unknowns. To make progress we have to explore and unmask causal connections. Whereas in the case of known unknowns, we can be much more strategic and deliberate. The known knowns paradigms simply call for operation efficiency and disciplined execution.

The greatest challenge to applying a rational methodology within irrational context is the keen awareness of shift in attention from deliberate application of set strategy to simple reactivity to environmental instigators.

July 20, 2020April 10, 2021

Scientific Inquiry

At its core AAPharmaSyn is a science company driven by pursuit of knowledge to the benefit of our clients. We are motivated and energized by the conceptual theater that houses pursuit of scientific truths and the primacy of empirical evidence to test hypothesis and subject results to peer review. We find it enormously rewarding to be able to produce a generalizable theory that encapsulates a wide range of observations. Herein we discuss general attributes of scientific inquiry that encompass our approach to solving a novel question with ambiguous link to established conceptual schemes. Due to the nature of our work we will refrain from commenting on social sciences and limit our scope to physical and life sciences.

Based on our experience the scientific inquiry requires incorporation of the empirically verifiable questions, direct investigation of the questions of interest and reproducible and generalizable results. These elements constitute a framework for scientific inquiry resulting in formulation of theories that have predictive, explanatory and operatory powers.

Empirically Verifiable Questions

Asking informed question is critical to making insightful discoveries. If questions do not lead to multiple conjectures that need to be tested and explored much knowledge is unlikely to be gained. On the other side of the sliding scale if the questions are too broad and contain ill-defined themes such as “What is the nature of the Universe” they will invariably lead to highly involved discussion without making discernable progress on the question that generated the discussion in the first place. Thus, a good scientific question allows multiple hypothesis to be tested and is rooted in empirical observation that can be reproduced on command. When we engage in discovery research, we are frequently asking what determinants are causing a specific outcome and how these determinants interact to produce desired result. To that end making an intriguing observation provides us with an inspiration to dig deeper.

Direct Investigation of the Questions is Possible

As Richard Feynman has note in his autobiography: “…you must not fool yourself – and you are the easiest person to fool”. This statement cannot be more true when the phenomenon is question is not directly observable. For example when investigating determinants of a specific behavioral phenomenon a researcher may make propose a hypothesis that is logically unverifiable by any available methods. Such as instead of relying on controlled stimuli and observing response patterns, one can envision infamous homunculus who is observing the observer and causes specific action to suit his desires. A researcher can spend much time in trying to decipher the hidden desires and ambitions of the homunculus as the subject is ripe with questions that seemingly can be afforded answers via indirect observation. One thing that researcher is clearly incapable of demonstrating directly is proving existence of the homunculus in the first place. Nonetheless human creativity is such that the homunculus theory can be infinitely modified to accommodate perceived challenges until the point at which the theory becomes incomprehensible. Thus, for a theory to have predictive valence, it has to befall to direct scrutiny of its observable determinants. Moreover the theory must avoid logical pitfalls of infinite regression and others similar fallacies such that it has a clear and explicit chain of reasoning.

Reproducible and Generalizable Results

If a theory has beautiful explanatory narrative but fails to make correct predictions, it has no utility beyond pure entertainment value. However if it lends itself to making predictions based on the interplay of various determinants and desired results are consistently observed, much value can be gained with further investigations. In our experience of synthesis methodology development we come across many new reaction schemes and have to make predictions based on triangulation of multiple imperfect concepts. Once we make a prediction and compare empirical and hypothesized outcomes, we make adjustment to the weights of different determinants and in some instances have to reconceptualize our view of specific methodology to accommodate empirical results. This process would not be useful if it was not for generalizability to other systems that share same or similar set of determinants such that our predictive accuracy is increased.

In pursuing our passion, we consistently face environmental instigators that induce self-referent theorizing. We believe this to be a natural and expected consequence of scientific pursuit and that, in general, people are psychologically predisposed toward connecting dots where they do not exist. We find it to be our responsibility to deliberately challenge our own thinking such that we deliver the most objective and rational solutions to our clients.

July 20, 2020April 7, 2021

Drug Manufacturing Considerations in the United States of America

Scientific Inquiry | AAPharmaSyn | chemistry outsourcing

The following white paper outlines FDA premise and guidelines to companies aspiring to engage in manufacturing of active pharmaceutical ingredients. The information presented is an introduction to the nuanced nature of the process and is not intended to be an authoritative treatise on the in and outs of the drug manufacturing rules and procedures.

The Center for Drug Evaluation and Research is a division of the U.S. Food and Drug Administration that monitors most drugs as defined in the Food, Drug, and Cosmetic Act. Some biological products are also legally considered drugs, but they are covered by the Center for Biologics Evaluation and Research. CDER established the Office of Pharmaceutical Quality (OPQ) to ensure a uniform drug quality program across all sites of manufacture, whether domestic or foreign, and across all human drug product areas – new drugs and biologics, generics, and biosimilars—and also over-the-counter drugs and compounded drug products.

CGMP refers to the Current Good Manufacturing Practice regulations enforced by the FDA. CGMPs provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities. Adherence to the CGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations. This includes establishing strong quality management systems, obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations, and maintaining reliable testing laboratories. This formal system of controls at a pharmaceutical company, if adequately put into practice, helps to prevent instances of contamination, mix-ups, deviations, failures, and errors. This assures that drug products meet their quality standards.

General CGMP Practices for finished pharmaceuticals are outlined below.

Organization and Personnel
The quality control unit shall be responsible for approving or rejecting elements involved in the drug producing process, drug products manufactured, processed, packed, or held under contract by another company.
Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions.
Personnel engaged in the manufacture, processing, packing, or holding of a drug product shall wear clean clothing appropriate for the duties they perform.
Only personnel authorized by supervisory personnel shall enter those areas of the buildings and facilities designated as limited-access areas.
Personnel with any health conditions that may have an adverse effect on drug products should not involved in the drug producing process.
Consultants advising on the manufacture, processing, packing, or holding of drug products shall have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained.
Building and Facilities
Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations.
There shall be separate or defined areas or such other control systems for the firm’s operations as are necessary to prevent contamination or mixups
Operations relating to the manufacture, processing, and packing of penicillin shall be performed in facilities separate from those used for other drug products for human use.
Adequate lighting shall be provided in all areas.
Adequate ventilation shall be provided.
Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product.
Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas.
Air-handling systems for the manufacture, processing, and packing of penicillin shall be completely separate from those for other drug products for human use.
Potable water shall be supplied under continuous positive pressure in a plumbing system free of defects that could contribute contamination to any drug product.
Drains shall be of adequate size and, where connected directly to a sewer, shall be provided with an air break or other mechanical device to prevent back-siphonage.
Sewage, trash, and other refuse in and from the building and immediate premises shall be disposed of in a safe and sanitary manner.
Adequate washing facilities shall be provided, including hot and cold water, soap or detergent, air driers or single-service towels, and clean toilet facilities easily accesible to working areas.
Any building used in the manufacture, processing, packing, or holding of a drug product shall be maintained in a clean and sanitary condition, Any such building shall be free of infestation by rodents, birds, insects, and other vermin (other than laboratory animals). Trash and organic waste matter shall be held and disposed of in a timely and sanitary manner.
There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail
Sanitation procedures shall apply to work performed by contractors or temporary employees as well as work performed by full-time employees during the ordinary course of operations.
Any building used in the manufacture, processing, packing, or holding of a drug product shall be maintained in a good state of repair.
Equipment
Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.
Any substances required for operation, such as lubricants or coolants, shall not come into contact with components, drug product containers, closures, in-process materials, or drug products so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.
Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination
Written procedures shall be established and followed for cleaning and maintenance of equipment
Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product.
Appropriate controls shall be exercised over computer or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel.
Filters for liquid filtration used in the manufacture, processing, or packing of injectable drug products intended for human use shall not release fibers into such products.
Control of Components and Drug Product Containers and Closures
There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures; such written procedures shall be followed.
Each container or grouping of containers for components or drug product containers, or closures shall be identified with a distinctive code for each lot in each shipment received.
Upon receipt and before acceptance, each container or grouping of containers of components, drug product containers, and closures shall be examined visually for appropriate labeling as to contents, container damage or broken seals, and contamination.
Each lot of components, drug product containers, and closures shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit.
Representative samples of each shipment of each lot shall be collected for testing or examination. Sample meets the appropriate specifications of identity, strength, quality, and purity shall be approved, otherwise will be rejected.
Components, drug product containers, and closures approved for use shall be rotated so that the oldest approved stock is used first. Deviation from this requirement is permitted if such deviation is temporary and appropriate.
Components, drug product containers, and closures shall be retested or reexamined as necessary, e.g., after storage for long periods or after exposure to air, heat or other conditions that might adversely affect the component, drug product container, or closure.
Rejected components, drug product containers, and closures shall be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable.
Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.
Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product.
Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use.
Standards or specifications, methods of testing, and, where indicated, methods of cleaning, sterilizing, and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures.
Production and Process Control
There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. It should include:
The batch shall be formulated with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient.
Components for drug product manufacturing shall be weighed, measured, or subdivided as appropriate, and the process should be supervised
Actual yields and percentages of theoretical yield shall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product.
All compounding and storage containers, processing lines, and major equipment used during the production of a batch of a drug product shall be properly identified at all times to indicate their contents and, when necessary, the phase of processing of the batch.
Major equipment shall be identified by a distinctive identification number or code that shall be recorded in the batch production record to show the specific equipment used in the manufacture of each batch of a drug product.
To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch.
Valid in-process specifications for such characteristics shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate.
In-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit, during the production process.
When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product.
Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.
Written procedures shall be established and followed prescribing a system for reprocessing batches that do not conform to standards or specifications and the steps to be taken to insure that the reprocessed batches will conform with all established standards, specifications, and characteristics.
Reprocessing shall not be performed without the review and approval of the quality control unit.
Packaging and Labeling Control
There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials; such written procedures shall be followed. Labeling and packaging materials shall be representatively sampled, and examined or tested upon receipt and before use in packaging or labeling of a drug product.
Records shall be maintained for each shipment received of each different labeling and packaging material indicating receipt, examination or testing, and whether accepted or rejected.
Labels and other labeling materials for each different drug product, strength, dosage form, or quantity of contents shall be stored separately with suitable identification. Access to the storage area shall be limited to authorized personnel.
Use of gang-printed labeling for different drug products, or different strengths or net contents of the same drug product, is prohibited unless the labeling from gang-printed sheets is adequately differentiated by size, shape, or color.
If cut labeling is used for immediate container labels, individual unit cartons, or multiunit cartons containing immediate containers that are not packaged in individual unit cartons, packaging and labeling operations shall include one of the following special control procedures:
Dedication of labeling and packaging lines to each different strength of each different drug product;
Use of appropriate electronic or electromechanical equipment to conduct a 100-percent examination for correct labeling during or after completion of finishing operations; or
Use of visual inspection to conduct a 100-percent examination for correct labeling during or after completion of finishing operations for hand-applied labeling. Such examination shall be performed by one person and independently verified by a second person.
Use of any automated technique, including differentiation by labeling size and shape, that physically prevents incorrect labeling from being processed by labeling and packaging equipment.
Labeling materials issued for a batch shall be carefully examined for identity and conformity to the labeling specified in the master or batch production records.
Procedures shall be used to reconcile the quantities of labeling issued, used, and returned, and shall require evaluation of discrepancies found between the quantity of drug product finished and the quantity of labeling issued when such discrepancies are outside narrow preset limits based on historical operating data.
All excess labeling bearing lot or control numbers shall be destroyed.
Returned labeling shall be maintained and stored in a manner to prevent mixups and provide proper identification.
Procedures shall be written describing in sufficient detail the control procedures employed for the issuance of labeling; such written procedures shall be followed.
There shall be written procedures designed to assure that correct labels, labeling, and packaging materials are used for drug products; such written procedures shall be followed:
Prevention of mixups and cross-contamination by physical or spatial separation from operations on other drug products.
Identification and handling of filled drug product containers that are set aside and held in unlabeled condition for future labeling operations to preclude mislabeling of individual containers, lots, or portions of lot
Identification of the drug product with a lot or control number that permits determination of the history of the manufacture and control of the batch.
Examination of packaging and labeling materials for suitability and correctness before packaging operations, and documentation of such examination in the batch production record.
Inspection of the packaging and labeling facilities immediately before use to assure that all drug products have been removed from previous operations.
Packaged and labeled products shall be examined during finishing operations to provide assurance that containers and packages in the lot have the correct label.
A representative sample of units shall be collected at the completion of finishing operations and shall be visually examined for correct labeling.
Results of these examinations shall be recorded in the batch production or control records.
To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability testing
If the drug product is to be reconstituted at the time of dispensing, its labeling shall bear expiration information for both the reconstituted and unreconstituted drug product
Homeopathic drug products, Allergenic extracts that are labeled “No U.S. Standard of Potency”, New drug products for investigational shall be exempt from the requirements of this section.
Holding and Distribution
Written procedures describing the warehousing of drug products shall be established and followed.
Quarantine of drug products before release by the quality control unit.
Storage of drug products under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality, and purity of the drug products are not affected.
Written procedures shall be established, and followed, describing the distribution of drug products.
A procedure whereby the oldest approved stock of a drug product is distributed first. Deviation from this requirement is permitted if such deviation is temporary and appropriate.
A system by which the distribution of each lot of drug product can be readily determined to facilitate its recall if necessary.
Laboratory Controls
Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.
For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release.
There shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms.
Any sampling and testing plans shall be described in written procedures that shall include the method of sampling and the number of units per batch to be tested; such written procedure shall be followed.
Acceptance criteria for the sampling and testing conducted by the quality control unit shall be adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release. The statistical quality control criteria shall include appropriate acceptance levels and/or appropriate rejection levels.
There shall be a written testing program designed to assess the stability characteristics of drug products:
Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability;
Storage conditions for samples retained for testing;
Reliable, meaningful, and specific test methods;
Testing of the drug product in the same container-closure system as that in which the drug product is marketed;
Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted.
An adequate number of batches of each drug product shall be tested to determine an appropriate expiration date and a record of such data shall be maintained.
For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be appropriate laboratory testing to determine conformance to such requirements. The test procedures shall be in writing and shall be followed.
For each batch of ophthalmic ointment, there shall be appropriate testing to determine conformance to specifications regarding the presence of foreign particles and harsh or abrasive substances. The test procedures shall be in writing and shall be followed.
For each batch of controlled-release dosage form, there shall be appropriate laboratory testing to determine conformance to the specifications for the rate of release of each active ingredient. The test procedures shall be in writing and shall be followed.
An appropriately identified reserve sample that is representative of each lot in each shipment of each active ingredient shall be retained. The reserve sample consists of at least twice the quantity necessary for all tests required to determine whether the active ingredient meets its established specifications, except for sterility and pyrogen testing.
An appropriately identified reserve sample that is representative of each lot or batch of drug product shall be retained and stored under conditions consistent with product labeling.
Animals used in testing components, in-process materials, or drug products for compliance with established specifications shall be maintained and controlled in a manner that assures their suitability for their intended use. They shall be identified, and adequate records shall be maintained showing the history of their use.
Records and Reports
Any production, control, or distribution record that is required to be maintained in compliance with this part and is specifically associated with a batch of a drug product shall be retained for at least 1 year after the expiration date of the batch or, in the case of certain OTC drug products lacking expiration dating
All records required under this part, or copies of such records, shall be readily available for authorized inspection during the retention period at the establishment where the activities described in such records occurred.
A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed.
Component, drug product container, closure, and labeling records shall include:
The identity and quantity of each shipment of each lot of components, drug product containers, closures, and labeling; the name of the supplier; the supplier’s lot number(s) if known; the receiving code and the date of receipt.
The results of any test or examination performed and the conclusion derived therefrom
An individual inventory record of each component, drug product container, and closure and, for each component, a reconciliation of the use of each lot of such component. The inventory record shall contain sufficient information to allow determination of any batch or lot of drug product associated with the use of each component, drug product container, and closure.
Documentation of the examination and review of labels and labeling for conformity with established specifications
The disposition of rejected components, drug product containers, closure, and labeling.
Master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person.
Master production and control records shall include:
The name and strength of the product and a description of the dosage form;
The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product, and a statement of the total weight or measure of any dosage unit;
A complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristic;
An accurate statement of the weight or measure of each component, using the same weight system (metric, avoirdupois, or apothecary) for each component. Reasonable variations may be permitted, however, in the amount of components necessary for the preparation in the dosage form, provided they are justified in the master production and control records;
A statement concerning any calculated excess of component;
A statement of theoretical weight or measure at appropriate phases of processing;
A statement of theoretical yield, including the maximum and minimum percentages of theoretical yield beyond requirement
A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling;
Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed.
Batch production and control records include:
An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed;
Documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished
All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup.
Laboratory records shall include complete data derived from all tests necessary to assure compliance with established specifications and standards, including examinations and assays
Distribution records shall contain the name and strength of the product and description of the dosage form, name and address of the consignee, date and quantity shipped, and lot or control number of the drug product. For compressed medical gas products, distribution records are not required to contain lot or control numbers.
Returned and Salvaged Drug Products
Returned drug products shall be identified as such and held. If the conditions under which returned drug products have been held, stored, or shipped before or during their return, or if the condition of the drug product, its container, carton, or labeling, as a result of storage or shipping, casts doubt on the safety, identity, strength, quality or purity of the drug product, the returned drug product shall be destroyed unless examination, testing, or other investigations prove the drug product meets appropriate standards of safety, identity, strength, quality, or purity.
Drug products that have been subjected to improper storage conditions including extremes in temperature, humidity, smoke, fumes, pressure, age, or radiation due to natural disasters, fires, accidents, or equipment failures shall not be salvaged and returned to the marketplace.

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Author: AAPharmaSyn