Dec 2019 - Jan 2020

Page 1

Vol - 14 • Issue - 5, Dec 2019 - Jan 2020



Dr. Tarun Chugh SIMco Pharma Consultancy, Ahmedabad At CPhI's Pharma Analytical Conclave 2019

India Pharma

News & Updates

Breakthrough status for anticancer kit First to launch generic Dydrogesterone tablets By launching its generic Dydrogesterone tablets for treatment of infertility and pregnancy related complications in the Indian market, Mankind Pharma has become the first Indian and second global firm to develop the drug. The company's product is generic version of Abbott's Duphaston tablets. The manufacturing process of Dydrogesterone is very complex as it involves conversion of natural progesterone. Progesterone is a natural hormone involved in menstrual cycle, implantation and in successful maintenance of pregnancy. Any deficiency of progesterone during different stages of reproductive process can cause infertility, menstrual disorders and miscarriage.

Biocon sixth among top 10 Global Biotech Employers Bengaluru-headquartered biopharmaceuticals company Biocon Ltd has moved up to sixth spot in the Top 10 Global Biotech Employers ranking for 2019. It continues to be the only company from Asia to feature on the prestigious USbased 'Science' magazine's annual 'Science Careers Top 20 Employers' list, since its debut in 2012. Ranked at number six among global pharma and biotech companies in 2019, Biocon has moved up from number seven in 2018 and number nine in 2017. The ranking is a result of the 2019 Science Careers Top Employers global survey conducted by the US-based Science magazine to determine which companies in the biotech and pharmaceutical industry have the best reputations as employers globally. Biocon was ahead of leading global pharma companies like Novozymes, Roche, Eli Lilly, Abbott, Novartis, Pfizer etc. in the 2019 rankings. The Top 5 global players in this year's list are Alnylam, Regeneron, Incyte, Merck KGaA and Spark therapeutics.

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The USFDA's Centre for Devices and Radiological Health has designated a medical invention by a Bengaluru-based scientist as a “breakthrough device� in liver, pancreatic and breast cancer treatment. Cytotron, developed by Rajah Vijay Kumar, aids in tissue engineering of cancer cells, altering how specific proteins are regulated to stop these cells from multiplying and spreading. Shreis Scalene Sciences is the company that had taken the device to the US. Devices will be made in India, given there are hardly any imported parts: Inventor Cytotron is intended to cause degeneration of uncontrolled growth of tissues. Kumar had developed Cytotron at the Centre for Advanced Research and Development, which is headquartered in Bhopal, after nearly 30 years of research into cellular pathways and interactions with specifically modulated fast radio bursts.

To reduce cost of insulin and cancer drugs Biocon Biologics is focusing on innovative business models to reduce the cost of human insulin and cancer drugs, as it looks to build a pipeline of 28 biosimilars across global markets. The company plans to create an ecosystem where patients not only have access to the right medicine, but also gets the right care without always reaching a hospital. The company said it does not want to emulate any particular model, but the idea of ensuring universal access to diabetes medicine or rh-insulin comes from the fact that even after 100 years of the patent being written off many do not have access. So far, four biosimilars of Biocon Biologics have been commercialised globally.

Global Pharma

News & Updates

AI-based drug discovery platform Artificial intelligence (AI) based drug discovery platform, Healnet from UK-based drug technology firm Healx, analyses rare disease data to predict and link therapies to rare diseases. Founded in 2014, Healx aims to develop treatments for patients suffering from rare diseases. Previously, Healnet identified eight repurposing drug candidates with the potential to treat fragile X syndrome. Many of the identified candidates showed efficacy in-vivo, while one candidate is being advanced toward a Phase IIa clinical trial. The AI-based drug discovery platform was also used in another project with the Pitt Hopkins Research Foundation to evaluate, predict and advance therapies for Pitt-Hopkins syndrome, a rare neurodevelopmental condition. In October, Healx raised $56m in a Series B funding round to support the development of rare disease treatments identified using Healnet. Healx plans to utilise the funds to bolster its pipeline, including fragile X syndrome therapies.

To discover drugs based on cellular behaviours Flagship Pioneering has launched a new company, Cellarity, to discover drugs based on insights from research of cellular behaviours. The company was established in 2017, developing a platform that uses single-cell technologies and machine learning to analyse cell behaviour. After digitising and quantifying cell behaviours, the platform understands the dynamics associated with those behaviours, using the information to develop therapies that can direct them. Cellarity builds on the concept that several diseases occur due to abnormal cell behaviours in a tissue. The company leverages this concept to quantita-

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Dec 2019 - Jan 2020

tively define changes in cellular behaviours related to disease and identify therapies that can restore their normal state. The information on cellular behaviours enables discovery of drugs that can concurrently act on molecular, cellular, phenotypic, organismal and clinical factors of a disease, instead of only a single target protein or pathway. The Cellarity platform features a combination of the company's physical laboratory and its digital technology, Cellarium.

To digitally transform manufacturing and supply chain Novartis has collaborated with Amazon Web Services (AWS) to digitally transform the manufacturing, supply chain and delivery of its medicines using cloud services. Under the multi-year partnership, Novartis will leverage AWS artificial intelligence (AI) and machine learning (ML) services for innovation and cost efficiencies of its business processes and systems worldwide. The companies will work together to develop Novartis Insight Centers, which will enable realtime visibility across the pharmaceutical company's manufacturing processes and distribution centres. Novartis will also use the Cloud service to capture inventory, quality and production data. The company can apply internet of things (IoT), analytics and ML for better visibility and efficiencies. Moreover, data scientists at the pharmaceutical company can explore new optimisation models to bolster the production of complex, personalised therapies. IoT services will be used for visual inspections of Novartis' manufacturing sites by creating images, which can be reviewed with computer vision algorithms to help track manufacturing risks. This real-time data is expected to facilitate informed decisions for efficient production and distribution of drugs in 155 countries.

Global Pharma

News & Updates

Blockbuster drugs become cheaper in China China's National Healthcare Security Administration (NHSA) has announced it has agreed an average 61% cut in prices of 70 topselling drugs with large pharma manufacturers in exchange for inclusion on a state-run insurance scheme list. According to the South China Morning Post, the 70 drugs include Roche's Perjeta, Novartis' Xolair and the top selling drug in the world AbbVie's Humira, as well as Eli Lilly and China-based Innovent Biologics' Tyvyt. State-owned news organisation Xinhua noted that 22 anti-cancer drugs, seven drugs for rare diseases, 14 for chronic diseases, four for paediatric indications and three for hepatitis were reduced in price by 87%. The NHSA claims this makes the prices of these drugs the lowest in the world. Also, this agreements means big pharma and their drugs will have greater access to the world's second largest pharma market because more Chinese citizens in smaller, more remote cities will be able to afford the drugs through their state medical insurance system.

NDA for drug indicated for multidrug resistant HIV ViiV Healthcare has submitted a new drug application (NDA) to the USFDA for its first-inclass human immunodeficiency virus (HIV) drug fostemsavir. This is based upon data from the pivotal Phase III BRIGHTE study, which tested the effects of combining fostemsavir with an anti-retroviral in a group of heavily treatment-experienced adults with multi-drug resistant HIV-1 infection. This combination demonstrated superiority to placebo at 96 weeks, according to results presented at the International AIDS Society conference in Mexico City earlier this year. Multi-drug resistance is a common issue in HIV

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treatment because the virus constantly mutates, and there are issues with tolerability and drug-todrug interactions in combination therapies for this condition. Fostemsavir has a novel mechanism of action; it binds directly to the glycoprotein 120 subunit on the surface of the virus, which blocks HIV from attaching to CDR+ T cells and other immune cells, so they cannot infect them and multiply. There has been no demonstrated resistance to this mechanism, which ViiV believes is why this treatment works in multi-drug resistant strains of HIV. ViiV has already received fast track and breakthrough therapy designation from the FDA for this drug, and are planning to submit applications to other regulators, including the European Medicines Agency, in early 2020.

Consortium to launch centre for regenerative therapies A consortium of academic, biotech, biopharmaceutical and healthcare partners in the US is set to create a centre to manufacture and engineer regenerative cancer therapies. Harvard University, Massachusetts Institute of Technology (MIT), GE Healthcare Life Sciences, Fujifilm Diosynth Biotechnologies and Alexandria Real Estate Equities will lead the consortium. MilliporeSigma, Boston Children's Hospital, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Massachusetts General Hospital and the Commonwealth of Massachusetts will also contribute. The $50m Center for Advanced Biological Innovation and Manufacturing is expected to be launched next year as an independent, non-profit entity. It will focus on cell and gene therapies, biologic discovery and manufacturing, immunotherapy, cell therapies and gene editing. The consortium aims to cut the time between research and clinical application.


Facts & Figures

DID YOU KNOW? Currently, more than 60,000 patients are participating in cell-based and gene therapy clinical trials globally. Low and middle income countries contribute to 80% of the global diabetes burden. Despite insulin's universal availability for the last 97 years, it is yet to be universally accessible. While the Indian pharm industry reached a size of $40 billion last fiscal, its exports stood at $19.2 billion. US market accounts for a third of India's pharma exports. The import of chemicals, intermediates and active pharmaceutical ingredients from China is now standing at around $2.5 billion a year. KRAS is a gene that suppresses the proliferation of cells. A mutated KRAS gene leads to cell proliferation causing cancer. KRAS mutations occur in 1 in 7 of all human metastatic cancers. India's medical device imports jumped 24% to Rs 38,837 crore in FY19, according to the latest export import data. The US is the largest exporter of medical devices to India, constituting one-fifth of the pie, followed by Germany, China, Singapore and the Netherlands. In 2018, 21.5 lakh TB cases in India were notified to the Revised National Tuberculosis Control Programme (RNTCP), a 16 per cent increase over 2017 and the highest so far. Statistics show that approximately 20-30% of leukaemia and lymphoma patients with remission after CD19 CAR T therapy experience relapse after a few years. In chimeric antigen receptor (CAR) T-cell therapy, patients' T-cells from the bloodstream are genetically engineered to identify and attack a specific cancer protein after reintroduction into the blood. Multinational drug company Mylan has invested more than one billion dollars in India to upkeep and expand the capacities during the last six or seven years. Chronic lung diseases are a group of diseases that target airways and other lung structures. Bavarian Nordic's Jynneos is said to be the first vaccine approved to prevent monkeypox worldwide. It is the only non-replicating vaccine to receive FDA approval for smallpox. The US Strategic National Stockpile (SNS) is the country's largest supply of pharmaceuticals and medical supplies for public health emergencies. The prevalence of retinal diseases is expected to rise globally over the next ten years as a result of ageing populations and the diabetes epidemic

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ASEPTIC PROCESSING AND STERILE MANUFACTURING Based on the presentations by Dr. Tarun Chugh, SIMco Pharma Consultancy, Ahmedabad, at CPhI's Pharma Analytical Conclave 2019.

Principles of sterilization and disinfection Sterilization is making a substance free from all micro organisms both in vegetative and sporing states. Spore is a reproductive structure that is adapted for dispersal and surviving for extended periods of time in unfavourable conditions. Spores form part of the lifecycles of many bacteria, plants, algae , fungi and some protozoa.

ticle or area free of contaminants, including microbial, chemical, radioactive and other hazards.

Classification of Sterilization Ÿ Physical Ÿ Chemical Ÿ Physio-Chemical

Physical: Sunlight, heat , radiation, filteration.

Terms used in sterilization Disinfection: The destruction or removal of all pathogenic organisms capable of giving rise to infection. Disinfection does not affect spore state organisms. Antisepsis: The term is used to indicate the prevention of infection, usually by inhibiting the growth of bacteria in wounds or tissues. This is done by the antiseptics. Chemicals or disinfectants which can be safely applied on skin or mucous membrane to prevent infection by inhibiting the growth of bacteria. Bactericidal agents / germicides: Those which able to kill bacteria. Bacteriostatic agents: Only prevent multiplication of bacteria, but they remain alive.

Heat: Dry heat, red heat, flaming, incineration, hot air oven, infra red, moist heat. Radiation: Non- Ionizing, Ionizing - Electro Magnetic (Gamma/ X-Rays), UV. Filtration: Earthenware, asbestos, sintered glass, membrane. Chemical: Liquid, Gaseous. Liquid: Alcohols, Aldehydes, Phenolic, Halogens, Heavy Metals, Surface active agents, Dyes. Gaseous: Ethylene oxide, formaldehyde, beta propiolactone.

Factors affecting the efficacy of Disinfection and Sterilization • Number and Location of Microorganisms. • Innate Resistance of Microorganisms.

Cleaning: Important preparatory step before sterilization or disinfection, by removing soil and other dirt.

• Physical and Chemical Factors.

Decontamination: The process of rendering an ar-

• Organic and Inorganic Matter.

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• Concentration and Potency of Disinfectants.

Dec 2019 - Jan 2020


Aseptic & Sterile

• Duration of Exposure.

Hot air ovens are electrical devices used in sterilization. The oven uses dry heat to sterilize articles. Generally, they can be operated from 50 to 300 C (122 to 572 F) . There is a thermostat controlling the temperature.

• Biofilms • Contact Time • Load Patterns

This is the most widely used method of sterilization by dry heat. Items: glassware, forceps, scissors, scalpels, all-glass syringes, swabs, liquid paraffin, dusting powder, fats, grease. (Materials should be properly arranged to allow free circulation of air).

Different types of sterilization Steam (Autoclave)

UV Light

Autoclave is a device that uses steam to sterilize equipment and other objects. This means that all bacteria, viruses, fungi, and spores are inactivated. However, prions may not be destroyed by autoclaving at the typical 134 C for 3 minutes or 121 C for 15 minutes. Principle: Water boils when its vapour pressure equals the surrounding atmosphere. Thus, when pressure inside closed vessels increases, the temperature at which water boils increases too.

Ultra violet disinfection in water system

Factors affecting the efficacy of Steam Sterilization (Autoclave) • Steam Quality (Pure Steam) • Heat Distribution • Load Pattern • D-Value (TS Cycle) • F0 Value

Holding period: varies. Temperature: between 108 C and 147 C. Items: dressings, instruments, laboratory ware, media and pharmaceutical products.

• Proper fixing and location of controlling probes

Dry Heat Oven

• Porous and Non-Porous load

• Exposure Time

Factors affecting the efficacy of Dry Heat Sterilization (Autoclave) • Heat Distribution • Load Pattern • DHS / Tunnel Integrity • FH Value • Exposure Time Vs Geometry Size • Proper fixing and location of controlling probes

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Aseptic & Sterile

Filtration Filtration helps to remove bacteria from heat labile liquids Items: sera and solutions of sugars or antibiotics. Principle: as viruses pass through the ordinary filters, filtration can be used to obtain bacteria-free filtrates of clinical samples for virus isolation.

Factors affecting the efficacy of Filtration method • Membrane pore Size (µm) • Properties of the liquid • Density, viscosity, corrosiveness etc. • Properties of the solid particle shape, particle size and distribution, compressibility of solid. • Proportion of solids in the slurry

Air Relief Valve

Pressure Gauge

Factors affecting the efficacy of UV Light Air Relief Tube

As the water passes through the cartridge, dirt and debris is trapped in the fabric.

• Power fluctuations • Burning Time • Preventive maintenance


Lower Manifold


Radiation There are two types of radiation: Ionising radiation and non-ionising radiation.

Cartridge Filters

Non-ionising radiation Infrared - used for rapid mass sterilization of prepacked items such as Syringe, Cathaters. UV - used for disinfecting enclosed area such as entryways, operation theatres and labs. Ionising radiation Electro magnetic (Gamma/ X-Rays) - used for sterilising plastics, syringes, swabs, catheters, animal feeds, cardboard, oils, metal foils, greases, fabric.

Factors affecting the efficacy of Radiations

HEPA Filter Membrane Filters Membrane filters are made of cellulose esters or other polymers. They are usually used for water purification and analysis, sterilization and sterility testing and preparation of solutions for parenteral use.

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• Improper validation (maintaining SAL) • Radiation Distribution and penetration (Dosage Gy) • Load Pattern • Chamber Integrity • Oxygen, Time and Temperature (MT45°C) • Exposure Time Vs Pack Size • Proper fixing and location of controlling probes

Dec 2019 - Jan 2020


Aseptic & Sterile

Analysing Different Facility Designs for Sterile Product Manufacturing Grades of clean areas, different HEPAs and airflows for aseptic processing, restricted access barrier systems and isolators, and clean room technology are discussed here.

Techniques Used Ÿ Traditional method Ÿ RABS Ÿ Isolation

Facility Designs

Ÿ Robotic Isolation

Facility designs are based on the final product, the route of administration, the manufacturing requirements, and the storage, handling and transport requirements.

Disadvantages of traditional methods In traditional methods, you are operating at high risk. Large amount of Grade A space is used when you are doing traditional activities. And there are increased operational costs as well.

RABS Advantages

Pharmaceutical Facility Requirements

Restricted access barrier system (RABS) is easy to install and validate. It is inexpensive, compared to the quality and cost. And you are able to downgrade the production area to Grade B.

RABS Disadvantages

Non-Sterile Drug Products

Sterile Products

Surrounding production area must be Grade B. There is no operator protection, no possibility to recycle the air inside, and no possibility to perform WIP cycles or auto-decontamination cycles.

Isolation Advantages Isolation ensures highest product protection. You will be able to downgrade production area to Grade C. The air inside isolator can be recycled – HVAC energy consumption savings. Medical Device Facility Requirements

It is possible to perform WIP cycles or automatic decontamination cycles. Enhanced automation/cost savings is the other advantage.

Isolation Disadvantages Isolators cannot be installed on existing machines. The purchase cost is on the higher side.

Robotic Isolation Advantages Class I

Class II

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Class III

Flexibility is the primary advantage of this new era technique in sterile manufacturing.

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Aseptic & Sterile

Faster equipment production – approximately 7 months (18 months typical Isolator), smaller footprint, less equipment to test and validate, quick changeover (1 hour), utility savings – no washing/oven, operator reduction and cost savings are the other advantages of robotic isolation. Artificial Intelligence (AI) is the add on of this technique.

formed other critical operations. Collecting (b)(4) water from the bottom of the filling machine to lubricate equipment, as mentioned above, also raises concerns about the design and qualification of your equipment.

Takeaway • Poor Designing

Robotic Isolation Disadvantages

• No Risk Assessment

• Small-scale solution

• Poor SOPs for sampling process

• Slower production

• Poor PQ of line as it was cleared for process without Risk assessment of CAPA

Case study Analyzing Different Facility Designs for Sterile Product Manufacturing


483 Observation Your facility design may represent an additional contamination risk to the products you manufacture. For example, we observed an employee crawling under filling equipment to get to the area where he per-

When the company was designed no thought process was given on Aseptic Handling and classification of clean area. QbD for process was not properly evaluated, and SOPs and training of clean area are lacking for clean area handling because of design constrains.

Contamination Control Policy

Influences on Contamination Non-product Contact Equipment

Tools & Utensils

Influences from Validation Adjacent Areas

Seasonal Effects

Facility Housekeeping & Sanitization

Equipment Design

In-Process Materials

Facility Design & Maintenance

Equipment Cleaning & Maintenance

Products Personnel Gowns & Hygiene

HVAC Design & Operation

Personnel Behaviour & Training

Storage Conditions Manufacturing or Filling Process

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Process & Cleaning Water

API or Assemblies

Raw Materials

Dec 2019 - Jan 2020

Product & Material Flow

Personnel Flow


Aseptic & Sterile

Assessing Contamination Risks A risk assessment should be made to determine any relevant contamination control factors that may affect the products or processes performed in the cleanroom. Some examples of methods used for determining and managing these factors include: Ÿ HACCP (Hazard Analysis Critical Control Point)

The most important points for risk assessment as per ICH Q9 are: Ÿ Identification – Done via investigation Ÿ Analysis – Ensure the risk is real or risk is not ig-

nored Ÿ Evaluation – Probable and root cause Ÿ Control by reduction measures and risk accep-

tance – remedial actions and CAPAs

Ÿ FMEA (Failure Mode Effects Analysis)

Ÿ Communication – Team work

Ÿ FTA (Fault Tree Analysis)

Ÿ Monitoring and Review – Effectiveness

Grades of Clean Areas

EU Annex 1

Maximum permitted number of particles per m3 equal to or greater than the tabulated size At Rest

In Operation


0.5 µm


0.5 µm



3 520


3 520



3 520


352 000

2 900


352 000

2 900

3 520 000

29 000


3 520 000

29 000

Not defined

Not defined

For classification purposes in Grade A zones, a minimum sample volume of 1m should be taken per sample location.

ple locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.

For Grade A, the airborne particle classification is ISO 4.8 dictated by the limit for particles ≥5.0 µm.

Open Cleanroom Concept ISO Class 5 (Class 100)

For Grade B (at rest), the airborne particle classification is ISO 5 for both considered particle sizes. .

Unidirectional Air Flow Cleanroom

For Grade C (at rest & in operation), the airborne particle classification is ISO 7 and ISO 8 respectively.

Unidirectional airflow is a way of ensuring air flows in only one direction, lessening the possibility of particles being kicked around and landing in your cleanroom.

For Grade D (at rest), the airborne particle classification is ISO 8. For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sam-

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In most cleanrooms, air is directed from the top of the room to the bottom, ensuring any contaminating particles are pushed out and don’t land where they’re not supposed to.

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Aseptic & Sterile

Open Passive RABS Expect more regulatory scrutiny for your smoke studies and EM with the type of barrier concept. No pressure differential between RABS and where operators are working

Open Passive RABS 7.6-15 cm gap between HEPA Filter and top of RABS Grade A ISO Class 5 In Operation & At Rest Unidirectional Air Flow

Grade B ISO Class 5 At Rest ISO Class 7 In Operation Non-Unidirectional Air Flow

Low Wall Returns

Problems with poorly implemented RABS Ÿ Only the LAF for the filling machine, nothing for

the room. Ÿ No pressure differential between RABS and where

operators are working.

any over pressurization of the RABS, the operator's breath or the billowing of the clean room suit could enter the RABS via these gaps. Gaps allow airflow from the Grade B to enter the Grade A environment. This can be tested by doing an investigative smoke study inclusive of a particle counter.

Ÿ Gap between filters causes turbulence.

Many RABS are poorly designed or often poorly implemented Most of the air supplied to the Grade B environment short circuits into the RABS air inlet, effectively decreasing the air mixing in the Grade B cleanroom. The Grade B environment often are not designed for ISO Class 5 design criteria. The Grade A air sweeps across the floor.

Door gaps in passive RABS are points for contamination Glove ports are positioned so that when the operator has one arm in each port, their body, and face are directly in front of a gap in the barrier. Without

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Aseptic & Sterile

483 Observation Dr. W. Whyte uses the four terms to provide estimate of risk

For example, you failed to perform adequate unidirectional airflow pattern studies (i.e., smoke studies) for the aseptic filling line used for the production of (b)(4) Injection. The smoke studies did not include examination of airflow during set-up and at points of process intervention. Moreover, your airflow pattern studies for the class 100 area of the (b)(4) filling line show clear evidence of turbulent airflow in your filling line located in Room (b)(4) both above the (b)(4) just prior to entry into the filling zone and over the stopper bowl adjacent to the filling zone. Although this lack of unidirectional airflow can compromise sterility, you failed to take appropriate action to ensure that your parenteral drug products were protected from these contamination hazards. An in situ air pattern analysis should be conducted in all critical areas under dynamic conditions, to demonstrate unidirectional airflow and sweeping action at critical work areas. These studies should evaluate the impact of aseptic manipulations (e.g., interventions) and equipment design, document the activities performed, and include written conclusions. In your response to this letter, provide a copy of your new smoke study recordings along with supporting documentation.

Equipment, smoke quality, manifold, camera angles make a difference in capturing airflow patterns!

0 = no risk 0.5 = Very low risk 1 = low risk 1.5 = medium risk 2 = high risk

Filling Risk Ÿ Vertical Laminar Flow - no barrier Ÿ Vertical Laminar Flow - curtains Ÿ Vertical Laminar Flow - hard enclosure Ÿ Horizontal Laminar flow Ÿ RABs Ÿ Isolator Ÿ Blow Fill Seal

Case Study: Poorly Designed Sterile Filling Line Cleanroom was qualified including air flow visualization studies. EM data from media fills (Settle Plates) were registering CFUs. The sample locations were suspect, however the picture tells us everything. No seperative airflow between the RABS and the operating personnel.

Process Risk Assessment A different way of looking at risk Risk from microbial contamination equals A x B x C x D where: A= Contamination arising from a source such as glove or airborne B= Ease of dispersion or transfer C= Proximity of source from critical area or process D= Effectiveness of control method (Barrier, sealed container, antimicrobials, etc)

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Aseptic & Sterile Contamination Risk Assessment


Reliance on Personnel


Filling in Passive RABS

Validation, Cleaning, Maintenance


Design issues, no pressure differential between Grade A and grade B environment

Filling in Active RABS

Validation, Cleaning, Maintenance


Improved design, pressure differential (10-15 Pa) and airflow

Filling in BSCs

Room design, airflows, proximity to other activities

Filling in Isolators

Certification, qualificaModerate tion, cleaning, location, level, maintenance Qualification, validated Low VHP cycle, Transfer of materials, maintenance (gloves gaskets, etc.)

Filling in Curtained areas

Cleaning, qualification, support areas

Very high

Flexible, swing, hard to clean, personnel in contact with unclean curtains, curtain material not validated for disinfection efficacy


Same as isolator


Same as isolator

Environmental Monitoring


Very High

Replenishing com- High ponents

Very High

Barrier or room design issues, sites not risk based, personnel not trained, equipment not adequate, media not adequate Design, personnel gowning, personnel behavior, airflow during this activity not known

Stopper jams


Very High

Defective seals


Very high

Size of container opening Length of time in exposure


Moderate to high


Moderate to high

Depends upon barrier, personnel and airflows


Design issues, Open vs close RABS or other barriers, control of environment Transfer of filled product to lyophilizer, manual vs automated Lophilizer cleanliness, and maintenance Depends on personnel technique, environment and design of equipment

Length of time clo- Low sure is exposed


If design is adequate and isolators adequately decontaminated with sterility assurance of transferred materials

Design, personnel gowning, personnel behavior, airflow during this activity not known Lacking inspection, surveillance and lack of operator training Depends upon filling speed as well as environment




Complex aseptic assemblies

Very high

Very high

Open product transfer

Very high

Very high

Protection of product from personnel and environment




Airflows, air velocity, placement of HEPAs if adequate




Placement, Tubing, gowning, training, media, equipment maintenance




Choice of chemicals and supplies, qualification testing very variable

Material Transfer



Material bioburden wipedown, transfer methods

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Aseptic & Sterile

Common errors that can lead to sterilization failure Ÿ Improper cleaning Ÿ Improper packaging Ÿ Sterilization load not adequately validated Ÿ Material compatibility Ÿ Dose audits

sterilization, testing, location, cleanliness of location, aseptic connections, airflow around aseptic connections, personnel practices during aseptic connection, cleaning inadequacy, hold times, etc.

It is practically impossible to prove that production equipment is “clean” at the level of 100%. Cleaning validation provides a means of proving that the contamination levels have been reduced below contamination acceptance limits.

Ÿ Sterility testing Ÿ Environmental Monitoring Inadequate Ÿ Room Bioburden not trended Ÿ Pre-Sterilization Bioburden mainly due to spore

formers Ÿ The misunderstanding that sterilization kills every-


The cleaning validation program should involve a rational monitoring program to maintain a validated state. Cleaning validation activity should cover: - active residue identification

Common Errors in Equipment and Components Cleaning Ÿ Critical components of the microbial reduc-

tion/elimination plan not well thought through. Ÿ Strategy not well defined for addressing microbial

contamination of parts and components. Ÿ Impact of raw materials, intermediates and APIs

not understood. Ÿ Effect of microbial load from materials, environ-

- active residue detection - method selection - sampling method selection - the establishment of residue acceptance criteria - methods validation - recovery studies - identification of equipment parts in direct contact with the product

ment and personnel not known. Ÿ Type of microbes hard to sterilize not considered. Ÿ Load of micro-organisms hard to sterilize not con-

sidered. Ÿ Biofilm formation not considered during develop-

ing cleaning validation.

Ÿ How much does each failure matter? Ÿ Can failures be predicted? Ÿ Consequences of the failure?

Ÿ Type of contamination vs choice of cleaning agent.

Ÿ What are the subsequent process steps?

Ÿ Method for testing may not be adequate.

Ÿ What is the contaminant?

Microbial Aspect of Cleaning Validation

Ÿ What can be done if a suitable proactive task cannot be found?

Things to be considered: What is the function of the equipment? What are the performance requirements? What can cause failures? Failures can cause due to design, cleaning, during

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Ÿ If a risk cannot be eliminated then how can it be reduced? Ÿ If the risk cannot be reduced how can it be monitored?

In Focus

Natoli Training

Tablet Training Event results in Successful Learning Experience Natoli Engineering, a global leader in tablet tooling manufacturing, held a one-day tablet compression training in two locations (Indonesia and Thailand) in November 2019. The event, which took place on November 14 in Indonesia and November 19 in Thailand, featured two significant learning experiences for development professionals in the pharmaceutical industry. The industry-leading training course provided a comprehensive, classroom experience in tablet formulation development and tablet compression tooling. The training featured Natoli professionals, Dr. Parthiban, Natoli pharmaceutical manufacturing consultant, and Yasar Shaikh, Natoli director of international business. Yasar said the event was a chance for successful thought leaders in the industry to get the learning experience they've always desired. “Since the event was selective, it gave highly motivated individuals in the industry to learn, thrive and grow in their business,� he said.

During the tablet formulation development segment, attendees learned about important topics in the tablet compression industry, such as basic principles of powder compaction, solid dose excipient selection, troubleshooting problems and scale-up challenges. The tablet compression tooling segment featured several important industry topics as well, such as international tooling standards, critical tooling check points, tooling steels and coatings and tablet design using TabletCAD. Natoli Engineering's TabletCAD is a free, webbased tablet design software that allows individuals to design tablets in-house with real-time validation. The software links directly to the manufacturing process so tooling can be shaped precisely to the models. An intuitive user interface guides the design process with helpful tips and real-time design validation. Natoli can provide customized training sessions at your location. For more information, contact Yasar Shaikh at

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Materials Handling

The Impact of Materials Handling on

Facility Design and Operation All too often the design of pharmaceutical OSD production facilities fails to recognise the impacton, and the opportunities for, materials handling. In this article, we consider a range of different options for materials handling, the benefits and challenges in each case, and the relationship between materials handling and facility design. Whereas the production processes themselves are easy to define and understand – for example, it is a straightforward task to design a room that fits a tablet press, even if the specific type of machine is undefined – there are many ways to feed to and from each process. In the case of a tablet press, the powders or granules can be tipped by hand or vacuum conveyed into the inlet of the machine, so a lower height ceiling is acceptable. Alternatively, drums or Intermediate Bulk Containers (IBCs) can be used to feed the tablet press by gravity. However, a taller room height would be a requirement to accommodate this system. A further option is to feed product from a mezzanine level or through-floor from a materials handling floor above – in this case the height of the compression room can be minimised, but a second production floor level needs to be considered in the facility design. At the output of the compression process there are more decisions to be made: Tablets can be received into small tubs, boxes or drums, or collected in larger IBCs within the room, transferred through wall for collection in an adjacent area, or fed through-floor for collection below. It may also be possible to connect the outlet of the tablet press directly to the inlet of a coater or packing machine. This example only considers one stage of the process

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– compression – however it illustrates the wide range of materials handling configurations that need to be considered and the impact that these decisions have on the overall facility design. On the other hand, if you already have an existing facility, then some of these materials handling options will not be available to you. In this case the challenge is to find the optimum materials handling solution that will fit in the space available. Whether considering a new production facility, or upgrading an existing one, the way that powders, granules, tablets and capsules are moved, stored, fed to and collected from processes has a fundamental impact on how the facility operates: its capacity, flexibility, expandability and cost of production.

Making the right decision at the right stage of the project Whether you are building a new production facility, or modifying an existing one, the chances are that you will have a good understanding of the process steps that are required at an early stage of the project. Once the process is defined, the next question should be 'How are the materials (i.e. the powders, granules, tablets and capsules) moved from one process step to another?', 'Do the materials flow easily without operator intervention?' and 'What is the best way to do this?'. All too often companies fix the facility layout without fully considering these fundamental questions – the result of which is to limit or compromise on the ideal materials handling solutions. With materials handling there is not a 'one size fits all' solution. Requirements can vary significantly from one project to the next. Factors such as production throughout, number of materials/SKUs, containment requirements, material characteristics,

Dec 2019 - Jan 2020


Materials Handling

building constraints and available budget all need to be taken into consideration to find the right materials handling solution.

What materials handling system is right for my facility? There are many ways to move materials through the production process. Three of the most commonly considered materials handling options are: 1. Continuous Processing 2. Handling in drums, tubs, boxes. 3. IBC Systems

Traditional materials handling approach using small containers

1.Continuous Processing Continuous processing is based on the simple concept of directly connecting the output of one process machine with the inlet of the next.For example, a tablet press (which by its very design is a continuous process) can be directly coupled to a continuous coater, the coater to the packing machine etc.

- Continuous processing restricts expandability of a system. For example, if there is a requirement to increase tablet production beyond the capacity of the existing line, then a completely new line is required (possibly requiring a new granulator, blender, compression machine, coater, packing machine etc.)

The benefits of this type of materials handling approach include:

2. Handling in drums, tubs, boxes etc.

- Materials transfer from process to process without 'materials handling'. - No connections or disconnections, so it can be particularly suited to the production of high containment products. - Less space required in the facility compared to a batch materials handling system. There are however some limitations with a continuous production approach: - The production process often involves both batch and continuous processes and connecting these types of different operations (for example, connecting a batch blender to a tablet press) may call for an intermediate buffer. - When several processes are connected, the system can only operate at the speed of the slowest process. - A shutdown of one machine (for maintenance, cleaning or due to a fault) results in the shutdown of the whole process line.

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Materials can be collected in small containers at the outlet of one process and manually moved and fed to the inlet of the next process. The powder containers can be tipped into the process by gravity or by use of vacuum transfer, which is also common in single floor facilities. Manual scooping is a popular way of transferring tablets. The benefits of this type of materials handling approach include: - Increased flexibility over Continuous Processing. By moving the containers to where the demand is, it helps balance out the flow of materials through the facility, maintains a reliable supply of material to the packing machines and, in doing so, achieves 'Continuous Manufacturing'. - Enabling 'Parallel Processing' to be carried out this means that processes operate in parallel at their optimum speed, giving the flexibility for any process to connect to any other process. By adopting a Parallel Processing approach, this would allow the output of one blender to feed to many tablet presses for example.

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Materials Handling

- Keeps the building costs low. The use of small containers and manual operations enables this approach to be used in single floor facilities with small production rooms. - Low capital cost for material handling as boxes, drums etc. are cheaper to purchase However, this traditional approach also has several disadvantages: - This is not a lean approach, as large numbers of containers mean lots of vessel movements, more connections/disconnections, additional cleaning and extra storage. - Limited production capacity, as the production batch is handled in many small sub-lots and requires lots of manual operations, with transfers being slow and inefficient. - Non-contained operation and open transfers increase the risk of contamination and crosscontamination. - Challenges to inventory control and traceability. As the batch is split into many small sub-lots, this requires manual activities to track each container and results in crowded GMP production areas. As the number of sub-lots increases then the risk for error escalates. - Labour intensive/reliant, with associated health and safety risks as operators often carry out manual lifting and handling of the containers and materials. - Container cleaning is more labour intensive due to larger numbers. This materials handling approach is normally seen in facilities – or areas of the process – where height and space constraints prevent other options being used. It can also be used where disposable containers are utilised, resulting in charges for safe disposal. Sometimes it is possible to upgrade these existing facilities with improved ways of handling powders, granules, tablets and capsules, focussing on bottlenecks in production and considering lean ways to handle materials. However, all too often the constraints of an existing building prevent the use of optimal materials handling solutions.

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3.IBC Systems IBC Systems enable the handling of larger batches in a single container, replacing the many drums, tubs and boxes. The benefits of IBC Systems include: - Fewer containers are required per batch. - Reduced movements of tablet containers.

IBC feeding to Tablet Press

- The number of connections/disconnections are reduced. - Less space is required for storage of containers (when empty and inter-process) - Reduced cleaning requirement. - More efficient and simpler traceability.

How many production floors? Having decided which materials handling methodology is most suitable, building design is then the next focus. All over the world, wherever new solid dosage facilities are being built, fundamental choices are being made between building a single-floor or multi-floor plant – and, if multi-floor, then how many floors? When land is expensive, it makes sense to consider building upwards rather than outwards with a larger footprint. The design of the new facility also needs to balance the future capacity requirements, as well as the requirements on 'day 1' whilst considering the higher investment costs now verses a high modification cost or missed opportunity costs later.

1. Single-floor facility In a single-floor configuration, IBCs can be used to connect one process to another. By matching the volume of the IBC System to the volume of the batch

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Materials Handling

processes, then full batch transfer can be achieved. This means that only one connection/disconnection is required between the IBC System and each process.

Single Floor Facility Process Flow

Single-floor facilities can have the lowest cost ofconstruction, but they have constraints with regards to the materials handling solutions. To benefit from direct gravity feed, pillar lifts are often used to position IBCs above each process, which means that you must allowfor enough height in the room design to allow the IBCs to be raised up. If the ceiling height is fixed, and too low, you will have to use methodology 2, of boxes and drums, which will require floor space to accommodate the number needed to process a batch.

Discharge to provide a dust-tight transfer and avoid the risk of contamination and cross-contamination. Alongside this, the correct solution for gently transferring sensitive materials through-floor also needs to be addressed. If poor material flow is a possibility, then methods of smoothly and consistently emptying containers must be considered without operator intervention.

Frames or mezzanines are alternative ways to achieve gravity feed in single-floor facilities if the building height and layout can accommodate this.

This two-floor arrangement also makes it possible to use larger volume IBCs, enabling production 'lots' to be consolidated into larger batch sizes for a leaner approach to manufacturing. As fewer IBCs are required, the number of IBC movements, connections/disconnections, cleaning requirements and storage space are all reduced.

2. Two floor facility

Multiple floor facility

As illustrated by the process flow diagram, a twofloor approach enables the top floor to be dedicated to materials handling and blending, with the tableting and packing processes taking place on the lower floor. In this case, pillar lifts are not required, and the height and size of the process rooms can be reduced significantly. The GMP production areas are less crowded and the smaller production rooms are lower cost to construct, maintain and clean.

Using more than 2 floors for production introduces a different type of concept: the ability to separate GMP process floors from technical materials handling floors.

The top floor can be an open materials handling floor. However, to achieve this, it is important to ensure closed connections before, during and after IBC

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The materials handling floors can have a lower area classification as the IBC Discharge Systems and IBC Filling Systems provide separation between the GMP and technical floors. Again, large sized IBCs are ideal for materials handling and can utilise the height of the rooms to maximum effect.

Dec 2019 - Jan 2020

Two Floor Facility Process Flow


Uhlmann Team

Bringing best-in-class to Indian shores On the occasion of Uhlmann India's new Office cum Assembly Shop premises opening in Pune on November 1st 2019, Pharma Machines & Technology caught up with Uhlmann management team for an exclusive interview.


Can you brief on Uhlmann India's initiatives to contribute to the overall growth of the pharmaceutical industry? Sumeet Arora: Indian pharmaceutical CSO & Managing Director, Michael Mrachacz (right), Director industry's scenario has changed drasti- Sales, Klaus Braig (left) of Uhlmann Pac-Systeme GmbH & Co. cally. Exports from India are increasing KG with Sumeet Arora, Managing Director, Uhlmann India. exponentially with a current contribution leads to faster resolutions, enabling our machines to of 30% by volume to US generics market alone. We run at a sustainable higher efficiency than any other have observed a trend in customers who are looking supplier. for high-speed and sophisticated equipment to serve the International Markets. But, their buying decisions How prepared is Uhlmann India to take up hinge on the Total Cost of Ownership (TCO), which complete integrated line projects in India? stay high due to higher cost of tooling imports over Klaus Braig: Uhlmann is a member company of the machine's long lifecycle. Our current setup will Excellence United, an alliance covering the entire facilitate to lower the tooling costs and thus, offer an value-added chain of Pharmaceutical production. attractive TCO. We have close relationships with our partners and How does the strategy for India fit in the have exchanged technical know-how on product overall global strategy of Uhlmann-Group? handover, forming a hassle free and continuous process. This has also been a unique selling proposition Michael Mrachacz: Uhlmann is the market leader for us, against our competition. This also enables us in high-class pharmaceutical packaging systems. to have factory-trained service people on-site and We bring the same Best-in-class quality equipment, project engineers to discuss new integrated projects. service support and digital solutions, to the Indian shores. Our equipment are ideally suited to match How prepared is Uhlmann India to cater to the dynamic customer requirements across both geFMCG / Non-Pharma Industries? ographies and demographics. Further, we have esArora: Uhlmann India also represents KOCH Pactablished a strong and dedicated Uhlmann Systeme in India. KOCH is a member company of Customer Service platform with 24/7 hotline that

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Dec 2019 - Jan 2020


Uhlmann Team

Uhlmann-Group, and has a clear focus and expertise on Sustainable Packaging for NonPharma applications. Most of our daily used products like toothbrushes, razors, electronic devices and other special nonstandard blister packing applications are the solutions offered at KOCH. We also offer packaging for Single use Eye lenses and medical grade sutures packs.


A number of challenges have been witnessed for serialisation in the packaging industry. To address such challenges, what are the solutions offered by your company? Arora: We offer our own equipment for Track & Trace, combined with the necessary software and hardware device for effective serialisation of product and enhanced traceability. We also offer serialisation solutions which can be retrofitted on existing equipment. Since 2008, we have developed our own inhouse expertise and skills in handling a wide variety of applications that are customized to every customer's processes. We have installed over 470 systems on a global scale. Today, we handle global projects, provide track and trace serialisation solutions across the different industry verticals.


IoT-enabled packaging is revolutionizing logistics industry and improving supply chain workflow. How do you define the role of IoT today, in the Indian pharma packaging industry? Mrachacz: The Indian industry will take some time to define the role of IoT. In Pharmaceutical Industry products are made in batches, and compounded with this are regulatory needs to be taken care of. Every batch requires having samples to be taken into labs. Currently, track and trace is a preferred solution for traceability. However, we are also developing IoT functions like predictive maintenance, comprehensive machine monitoring systems and have hired

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Dec 2019 - Jan 2020

Uhlmann India's new Office cum Assembly Shop On November 1st 2019, Uhlmann India's new Office cum Assembly Shop premises in Chakan, Pune, opened its doors to their clientele across India for the supply of 'Made in India' Change Parts. Aimed at supplying high quality precision Change Parts and faster turnaround service support, the full-fledged functioning unit is welcome sight for many Indian pharma giants. The facility was inaugurated by Mr. Parminder Dureja, Additional Director of Serum Institute of India, notably one of the largest vaccine manufacturers of the country. Michael Mrachacz, CSO & Managing Director, Uhlmann Pac-Systeme GmbH & Co. KG; Klaus Braig, Director Sales, Uhlmann Pac-SystemeGmbH & Co. KG; and Sumeet Arora, Managing Director, Uhlmann India, were present. Uhlmann India is headquartered in Pune with regional presence in Mumbai and Hyderabad.


Uhlmann Team

Uhlmann India's moment of pride people with similar skill sets. It can be said that the pharmaceutical industry will not be a forerunner, but will have IoT's presence eventually. Uhlmann is prepared and ready for the future, today.


What is the role of Digital Solutions in the Pharma packaging industry? How do you see it apply in the Indian context? Braig: Our world is becoming more and more digital. That makes communication less dependent on time and place. We see many opportunities in this development. The location is also no longer an issue when it comes to training employees. Your personnel can build up pharmaceutical packaging know-how – anytime and anywhere – using our digital training platform LEON. This platform complements “classroom” instructions provided and enabling participants to steadily improve their skills anytime, anywhere – without having to release machines from production. What does your tagline “Beyond Packaging” emphasize? Mrachacz: Our mission BEYOND PACKAGING stands for our new, far-reaching goals. We access markets outside the pharmaceutical industry and go

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beyond mere packaging with our services and digital solutions. We always look outside the box and set impulses for our customers and the industry. What are the challenges in your sector, globally as well as in India? What is your view on the market potential in India? Arora: India continues to have a strong position in the Pharmaceutical Industry. We are poised to hit 50 billion dollars by 2020. We are also exporting 20% of the entire generics produced in the world. Most of our supplies are to the western world and thus the challenges include high levels of compliance and regulatory requirements. Reliability is another prerequisite. Industry wants more tech-savvy equipment with better reliability. Uhlmann has a wide range of solutions for the same. What are your future plans for India, in terms of business expansion and market potentials in short, medium and long term? Mrachacz: As we grow our business In India, we will add more added-value to the pharmaceutical packaging systems that we supply. Also we plan to capitalise on the software strengths available in India. We would explore developing software systems in India at an optimum cost and pass the benefits to our clients.

Dec 2019 - Jan 2020


EBM Event

Pharma Brand Protection & Packaging 2019 Eminence Business Media's maiden “Pharma Brand Protection & Packaging 2019” summit successfully concluded on August 29th & 30th, 2019, at Hotel Novotel, Mumbai The theme of the summit was “Trends that have revolutionized the Pharma Packaging World”.The event had 150+ delegates attending the conference with Karomi Technologies, Autoprint Machinery Manufacturers Pvt. Ltd, Condot Systems, Original 4 Sure, Great Four Systems Pvt. Ltd., Bobst India, Novel Automation Ltd., Bullion Flexipack Pvt. Ltd, Pharma Secure, AptarPharma, NiproPharma Packaging, Systech International, Immer Group, Sun Packaging, Nuplas Industries, Pharma Mantra, GS1 India, PCRI & ASPA partnering the event. The two-day event ensured the continuous engagement of the audience, speakers and exhibitors through networking activities and discussions on the ever-evolving challenges of the pharmaceutical companies with regards to packaging and brand protection and how to overcome those challenges. The event saw as many as 15+ sessions and a panel discussion over the two days, attended by the CEO's, MD's, CXO's, Presidents, Sr. VP's, VP's, Directors, Associate Directors and Functional Heads of Packaging, Procurement, Quality Assurance / Quality Control, R&D, Regulatory Affairs, Manufacturing and Production and Supply Chain of the pharmaceutical and biopharmaceutical manufacturing companies. The day started with Ms. Guneet Kaur Hayer, Managing Director, Eminence Business Media, wel-

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coming all the delegates and thanking all the partners for their contribution towards the event. She also spoke about Eminence Business Media's vision on Pharma Brand Protection & Packaging. The event was inaugurated with the opening remarks by the chairperson Mr. Chakravarthi AVPS – Global Ambassador of World Packaging Organization in the presence of various eminent personalities from the pharma industry. He presented a bird's eye view of where the Indian packaging industry is heading in the pharma sector. The opening remarks were followed by the presentation on Interactive Packaging and it's Generation, Development & Evaluation by Mr. Sanjay Dave, CCO – Anfarnd Consultancy and former Head R&D Packaging, Cipla Ltd. The other presentations on day one included: "Are you equipped enough to design a Global Artwork Management System by Mr. Saravanan TJ, Director Packaging Quality, Biocon Ltd; Ensure Brand Consistency and Automate your Packaging Artwork Management Process by Mr. Vilva Natarajan, CEO, Karomi Technologies Pvt. Ltd; How QR Codes help in Product Verification & Diversion Control by Mr. ArshKabir Singh Gujral, Head of Sales, Original 4 Sure; How is Primary Packaging Market shaping up

Dec 2019 - Jan 2020


EBM Event

for Pharma by Prof. Braj Kumar Karna, Director, Packaging Clinic & Research Institute; Pharma 4.0 Automation: Packaging goes Digital with Industrial IoT by Mr. Srinivas Reddy Gurram, CTIO Technology Innovations, MST Sicherten; Is your QA/QC team working on maximum automation, match up with Industry 4.0 and avoiding recalls by Dr. Udaykumar Rakibe, Founder Pharma Mantra and Former Sr. VP Quality, Wockhardt; Checkmate – Carton Inspection Machine – ensures 100% defect free cartons by Mr. Ashok CN, Managing Director, Autoprint Machinery Manufacturers Pvt. Ltd.; What impacts USP 661.1 & ICH Q3d have on packaging material qualification by Mr. Soumyanath Mishra, Head Packaging Development, Mankind Pharma; How regulations and Compliance strengthen packaging resilience, Mr. Chandi Prasad Ravipati, Sr. GM Packaging Development, Aurobindo Pharma. Day one also witnessed a panel discussion on “Are we impacting packaging Quality in the rush to save on cost and Inefficiency” with panel members including Mr. Sanjay Chavan, Head Procurement of Packaging Asia, China, JPac, Sanofi Ltd; Ms. Tripti Nakhare, Sr. GM Regulatory Affairs and PDD, FDC Ltd; Dr. Udaykumar Rakibe, Founder, Pharma Mantra; Ms. Neeta Jha, Director Quality Operations, Johnson & Johnson ; Mr. Sateesh Pandey, Global Head Packaging Development, Alkem Labs; and Mr. Chakravarthi AVPS, Global Ambassador, World Packaging Organization, as the panel moderator. The sessions on day two included: What does Serialization mean to your business by Mr. Ajay Bapat, Head Packaging Development, Emcure Ltd; How to choose appropriate software and hardware for Track & Trace by Mr. Jigish Chiniwala, CMD, Condot Systems Pvt. Ltd; Beyond Serialization: Role

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of Data Collection and its unique utilities by Mr. Madhav Zaveri, Director and IT Business Partner for Quality, Cipla Ltd; What is the role of packaging and labeling in Supply Chain Efficiency by Mr. Prabir Das, Head Packaging Development, Mylan Labs; End to End Traceability using GS1 Standards by Mr. Bijoy Peter, Head Technical Services, GS1 India; Anti-Counterfeiting: A Major Concern by Mr. Pradeep Dhargalkar, Head Packaging Development, Unichem Labs; and a special discussion session on "Are your current packaging software future ready" by Mr. Bharat Kumar Reddy Gujavarthi, Vice President Operations, Great Four Technologies Pvt. Ltd along with Mr. Muntajeebuddin Mubashir, Head Sales, Great Four Technologies Pvt. Ltd and Mr. Sanjeev Mishra, Head Packaging Development, JB Chemicals & Pharmaceuticals Ltd. Day two of the summit also witnessed a special networking session for the event partners where they interacted with all the delegates in the conference hall and presented their solutions and services. Eminence Business Media organized a special activity for rejuvenating the attendees and partners on day two of the event. The event was concluded with the closing remarks by the Chairperson, Mr. Chakravarthi AVPS, followed by a group photo of the delegates and event partners of the event.

Dec 2019 - Jan 2020

In Focus

CAM Machines

THE CUTTING DIE FOR CAM BLISTER MACHINES WITH POSITIVE LOGIC REJECTION Main benefits and characteristics of the cutting die for CAM blister machines with positive logic rejection, called SLP GOOD BLISTERS ONLY The new cutting die designed by Partena, the CAM manufacturer specialising in the design and construction of blister machines, deposits only compliant blisters on the outgoing belt; any rejections, incomplete and empty blisters are expelled before the machine outfeed belt, with the optional possibility of separating the waste into different containers. Furthermore, the new cutting die device has been studied and designed with the intention of guaranteeing: Ÿ Product quality

The quality of the blister is also guaranteed in the event of stoppage; in fact, when the machine stops, the blisters in the yielding roller would risk remaining for an excessively long period in a curved position, with consequent deformation that could be problematic for the machine feeder downstream and in any case with the risk of causing discontinuity with respect to the other blisters that have been processed correctly.

Ÿ Proper and reliableoperation

For this reason, in the event of stoppage, the tension on the belt is removed to avoid excessive bending of the blisters.

Ÿ Automatic compensation of machine speed varia-

Easy and Quick Format Changeover

Ÿ Easy and quick format changeover


Product Quality

CAM has designed and developed the cutting die seeking to limit the format parts. For example, created with the same cutter, they share the same rotary gripper and the same guides, and for standard size blisters the SLP outfeed belt has an adjustable position. In this manner it can be adapted without the need to construct format parts.

The precision of the cutting position is guaranteed by sensors placed before the cut that read the position of the cavities with precision; also thanks to the constant reading of the blisters the system is able to detect any systematic errors of position, correcting them and showing on the operator panel the graphical trend of the detected errors.

Furthermore SLP is equipped with a system that reads the position of the thermoformed tape. Upon format changeover, all that is needed is to pass a stroke under the reading system that will recognise the blisters and their position and will automatically set the position of the cut, without the need for any manual adjustment.

Ÿ Standardization and reduction of the types of com-

ponents Ÿ Optimization of the primary area Ÿ Maximum flexibility for maximum efficiency

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Dec 2019 - Jan 2020

In Focus

CAM Machines

Finally all the parameters can be programmed from the operator panel or by graduated systems that guarantee a high level of ease and repeatability of format changeover, so that it can be performed by any operator. For example, the barrier photocell that records the rejection can be programmed directly from the operator panel by entering the format of the stroke without having to perform any manual adjustment.

Proper and Reliable Operation A system to control the torque required on the cutting motor shaft guarantees correct operation of the unit: if the torque is outside the determined range, the system warns the operator and immediately stops the machine.

Automatic compensation of machine speed variations SLP is independently motor-driven, so its connection to the other stations of the machine does not feature a fixed ratio: SLP automatically adjusts its speed and consequently slows down or accelerates, depending on the progress of the stations upstream. Moreover, thanks to the separation of the mechanical cutting cycle from that of the thermoforming machine, the cutting die can be stopped immediately, without having to complete the cuts of the stroke, with consequent release of the relative blisters on the belt.

Standardization and reduction of the types of components The logic of the rejection system is managed by the PLC rather than by the vision system, potentially al-

SLP integratd in the nMX blister packer

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SLP detail view lowing interfacing with a greater number of vision system suppliers.

Optimization of the primary area The SLP is both available in the integrated version within the blister packer basement and in the standalone version. The stand-alone version is particularly interesting for those production solutions requiring the separation between the primary and secondary phases by means of a cleanroom. In fact, the standalone version of the cutter permits to keep the only phases necessary to pack the product in blisters on the controlled atmosphere blister packer, and sends a continuous belt of blisters to the secondary area with the product already sealed. The blister machine without blister cutting reduces its length by about one meter. The result is a cleanroom with optimized dimensions, hence a reduction in production and management costs, as well as a simpler handling of the product leaving the cleanroom itself.

Maximum flexibility for maximum efficiency Only compliant blisters can leave the blister packer, and this permits to easily arrange a blister recovery system if the cartoner stops. In fact, should the cartoner stop for any reason, the SLP would automatically reverse the running direction of the outfeed conveyor belt in order to recover the blisters on a temporary storage system; the blisters thus recovered can be inserted again in the packaging cycle, so that to grant the maximum line efficiency. This operation mode will be even more important if the line has also to produce small lots.

Dec 2019 - Jan 2020


DSCSA Compliance

VERIFICATION ROUTER SERVICE Tackling DSCSA Compliance in Saleable Items Returns


here is a palpable relief within pharmaceutical industry as the deadline for DSCSA's requirements for saleable returns has extended by a year. The deadline has been extended till November 2020. Understanding VRS As part of compliance with DSCSA, it is mandatory that all prescription drugs returned to wholesale distributors have product identifiers on packages of saleable returned product verified with the manufacturer before being resold. Specific requirements include quarantine and investigation of a product determined to be a suspect product and quarantine, disposition, and notification of a product determined to be an illegitimate product (Section 582 of the FD&C Act). VRS is an interoperable solution used to manage the acceptance, formatting and delivery of requests and responses in order to support DSCSA verification requirements.

Ÿ Wholesaler/Distributor submit verification request in the sys-

tem. Ÿ Router service puts look-up directory in action to match the

required product information and direct it to the source. Ÿ Manufacturers respond to the verification request as an automated system.

Blockchain as VRS enabler Enterprise blockchain enables secure and immutable copy of a transaction to be formed by enabling a consensus driven logging and registration of a transaction. To update or change a transaction all parties need to agree to change the record and so no single party can change a record on their own. This eliminates fraud and counterfeiting as there is no single point of failure. While blockchain provides a possible solution for end to end traceability of product consignments (which is the end objective of DSCSA 2023), VRS requirement could be easily integrated into existing enterprise blockchain solutions to enable compliance with DSCSA 2020 VRS requirements. This would be a 2-step process:

According to industry estimates, based on the nature of drugs and their origin, 2-4% of all sold drugs are saleable returns. This constitutes thousands of transactions per day for some of the large distributors. VRS implementation and streamlining would enable distributors to resell returned items in shorter time while conforming to DSCSA requirements. The onus on providing timely verification on saleable item to the distributor, when requested, lies with the manufacturer. This is where complexity comes in. Reconciling data at large scale is a complex and time-consuming process. Often, product data is stored in diverse and dispersed systems that do not talk to each other. Manual intervention is costly, time consuming and prone to errors.

Blockchain enabled access would keep the data secure, immutable and consistent.

Industry Requirements

Challenges in VRS implementation

As David Colombo, Director, Life Sciences Advisory Services at KPMG, LLP, noted at healthcare packaging industry seminar, “To meet DSCSA milestone in 2019/ 2020, we need something efficient, effective and electronic. This has given rise to an immediate need for manufacturers to work with solution providers. According to an instant poll conducted at the seminar, when asked how they plan to respond to verification requests, 62.4% respondents stated they planned to use VRS provided by solution providers (against 8.3% who believed they could internally meet this requirement).

1. Lack of understanding of this key DSCSA requirements by key industry stakeholders 2. Concerns around interoperability of data lying in disparate systems 3. Most of the solutions available in the industry are in their infancy and are still being tested 4. Complexities in use cases 5. Limited time left to implement, test, roll out systems and train staff

On the distributor side, the “Big 3” pharmaceutical distributors, who account for more than 90 percent of all revenues from drug distribution in the United States: Amerisource Bergen Corporation, Cardinal Health, Inc. and McKesson Corporation, have all stated that they will not accept nonserialized returned products, also known as saleable returns, after November 27, 2020. For the VRS system to work seamlessly, the following steps need to work with precision and predictability:

Conclusion: Compliances are meant to protect end consumers and patients. Industry stakeholders often look upon compliance as the necessary pain to get their products out in the market in the shortest possible time. This means they often leave this important requirement until very late. November 2020 is sooner than it seems and the clock is ticking for manufacturers. Solutions are available but the intent and decisions will need to come from manufacturers.

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Step 1: A solution provider would write APIs to 'collect' data residing in different systems and diverse formats in a uniform interface automating access of data from manufacturer side. Step 2: A request would launch a look up program to match requested data against manufacturer database.

Dec 2019 - Jan 2020

Article contributed by: Tongadive

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