Issuu

Vol-18 Issue#4 Oct-Nov 2023

BIMONTHLY UPDATE ON QUALITY MOVEMENT

Pharma GMP & Quality Management

Ensuring Quality and Compliance in Controlled Environments

Top Trending Drug GMP Issues

INCREASE TABLET PRODUCTION A De nitive Guide to MULTI-TIP TOOLING

Hygienic design

PUMPS, SEALS AND VALVES Part 3

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Vol - 18 Issue - 4 October-November 2023

C ONTENTS

Dear Pharma Pals,

EXCLUSIVE

The pharmaceutical industry is under increasing pressure to

adopt Good Manufacturing Practices and produce highquality products. However, many companies have failed to properly implement "Schedule M", leading to issues during inspections of manufacturing plants and public testing labs.

PHARMA GMP & QUALITY MANAGEMENT

These issues include poor documentation, lack of process and analytical validations, absence of quality failure investigation, absence of internal product quality review, and faulty design of manufacturing and testing areas, among others. To address these concerns, the magazine has highlighted the "Top Trending Drug GMP Issues". Good

Top Trending Drug GMP Issues Exclusive on the most recent trends and challenges encountered by the pharmaceutical industry - by Sanjit Singh Lamba

Manufacturing Practices (GMP) is a system that ensures products are manufactured and controlled according to quality standards to minimize risks associated with

ARTICLES

pharmaceutical manufacturing. GMP is a part of a quality

management system that ensures produc ts are manufactured and controlled to quality standards that meet

INCREASE TABLET PRODUCTION

their intended use and market approval requirements. The article also discusses the importance of hygienic design for pumps, seals, and valves, as well as quality by-design and its

A Definitive Guide to MULTI-TIP TOOLING

regulatory implications. Last the most important to increase production and minimize downtime cost-effectively and efficiently, multi-

By Kevin Queensen, Mechanical Engineer (B.S.M.E.), Natoli Engineering Company

tip tooling is the way to go. Although it may be seen as

modern, multi-tip tools have actually been used since tablet presses emerged. Single-station presses used to dominate production, yet they could not keep up with the growing demand due to their limited tooling stations.

Part 3

Harjit Singh Dhaul

Publisher & Editor

Hygienic design PUMPS, SEALS AND VALVES

The third article highlights the hygienic design considerations of pumps, seals, and valves - By Tim Sandle

EDITORIAL ASSISTANT Ravlin Kaur PUBLISHER & EDITOR

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“Revision of Schedule-M"

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Printed & Published by: Harjit Singh Dhaul on behalf of Global Vision and printed at Hariom Printers, C/70, Akurli Industrial Estate, Akurli Road, Kandivali East, Mumbai 400 101, and published at 26-B, Rebellow Cottage, Gaon Devi Road, Poinsur (E), Kandivli 400 101. Editor Harjit Singh Dhaul.

8 12

76 78

DID YOU KNOW?

News & Updates

INDIA PHARMA Investment of Rs 6k cr approved by Centre under PLI scheme for pharma, medical devices sectors: Union Home Minister

Anil Matai as the new director general of OPPI The Association of Drug Makers of India (OPPI), the business body that addresses worldwide global (MNC) drug organizations, on Monday reported the arrangement of Anil Matai as its chief general. Anil Matai, a carefully prepared general administration proficient, has worked across MNCs including initiating tasks of Novartis India Ltd, GSK India, and Worldwide Pharma, Dubai. Subsequent to superannuating as overseeing head of Zydus Medical care, Anil was locked in as senior counsel Life Sciences at IQVIA Counseling and Data Administrations India Pvt. Ltd., and most as of late as

The Centre has approved investment of Rs 6000 crore in the pharmaceutical and medical device manufacturing sectors under the production linked incentive (PLI) scheme said Union Home Minister said here on Saturday. Shah was addressing a gathering after dedicating the newly built campus of the National Institute of Pharmaceutical Education and Research (NIPER) at Gandhinagar. "The Union government has taken a holistic approach and begun the process for the development of a cost-effective, sustainable and affordable process for 16 APIs (active pharmaceutical ingredient) and two KSMs (key starting material). The government has built three bulk drug parks with a total cost outlay of Rs 3000 crores, he said.

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Many high-risk medical device manufacturers stop production According to the new regulation, medical devices belonging to these categories, such as ventilators, imagining equipment, oxygen therapy equipment, nebulisers, x-ray equipment, surgical robots and oncology treatment linear accelerator, can't be sold from October 1st without a manufacturing license. Several of these manufacturers said they had filed for a licence in July but were still awaiting audits on the basis of which they will be given license. Medical devices supply chain disrupted for moderately high-risk and high-risk (class C and D) devices in absence of manufacturing licences, which have not been issued to even those manufacturers who had registered and sought a licence.

PHARMA machines & technology

April - May 2023

Pharma industry needs to focus on innovative products to achieve global leadership Worldwide MNCs burn through 20-25 percent of their benefits in examination and advancement while for Indian organizations the normal is around 10 percent for every year. Till the time we don't emerge with researchdrove creative items, we can't lead the fragment universally. The Government said the public authority needs to make the pharma business confident by 2047and the public authority has been working intimately with the business and the scholarly world to achieve the progressions in the home ground pharma industry to lead it to administrative role. The Branch of Drugs (DoP) told the Public Strategy on Exploration and Advancement and Development in the PharmaPrescription Tech Area in India in August this year. The strategy means to empower Research and development in drugs, including customary meds, phytopharmaceuticals and clinical gadgets. It recognizes the requirement for more noteworthy accentuation on

News & Updates

INDIA PHARMA empowering Research and development through natively created items and advancements across the worth chain in order to support worldwide seriousness. The Service of Synthetic compounds and Composts additionally officially revealed the Plan for Advancement of Exploration and Development in Pharma MedTech Area (PRIP), which expects to change the homegrown pharma and clinical innovation area from cost-based to development based development by reinforcing the examination framework in the country. NITI Aayog part V K Paul said the arrangement alongside different drives like PLI plans for the pharma area is supposed to change the whole pharma area scene. ICMR Chief General Rajiv Bahl named the Public Approach on Exploration and Improvement and Development in the Pharma-Prescription Tech Area as noteworthy. "This is presumably the main plan we have likely found in the beyond quite a long while," he expressed. The Indian drug industry is the third biggest drug industry on the planet by volume with an ongoing business sector size of around USD 50 billion. Going ahead, the business might actually develop to USD 120130 billion over the course of the following ten years.

India mandate to audit of pharma suppliers by drugmakers India's government drug controller, the Focal Medications Standard Control Association (CDSCO), has passed an order on compulsory reviews for natural substance and bundling material providers. The WHO and other wellbeing organizations have linked defiled India-made hack syrups to the passing of 70 kids in Gambia, 65 in Uzbekistan and around six in Cameroon over the last year. Drugmakers must do a review of their unrefined substances and bundling material providers "no less than once in a year" and must inform their permitting specialists of all item reviews. The exchange service has been holding studios to survey the administrative viewpoints on DEG pollution and examine the ongoing guidelines set up to forestall it.

announced that pharmaceutical companies having an annual turnover of over 250 crore will have to mandately adopt Good Manufacturing Practices (GMP) within six months. Companies with a turnover of less than 250 crore will have to do so in a 12-month time. The draft of Schedule M of the Drugs and Cosmetics Act has been approved and implemented, and there are around 10,500 manufacturing units in the country out of which 8,500 fall under the MSME (Micro, Small and Medium Enterprises) category. Drug regulators inspected 162 units and 14 public testing labs, and major issues found during inspections were poor documentation, lack of process and analytical validations, absence of quality failure investigation, absence of internal product quality review and faulty design of manufacturing and testing areas. To keep pace with the fast-changing manufacturing and quality domain, there was a need to revisit and revise the principles and concept of GMP mentioned in current Schedule M. This would bring the GMP recommendations and compliance expectation at par with global standards, specially to those of WHO, and ensure production of globally acceptable quality of drug.

Multinational clinical trials of new drugs overrecruiting Indians The ethics committees of medical colleges and hospitals are panels of doctors, social scientists and legal experts tasked with scrutinising proposals for clinical trials and determining whether the trials are justified, the risks to the volunteers are within acceptable limits, and informed consent has been obtained from the volunteers. Health sector analysts say that India accounts for just 3% of clinical trials globally and contributes 15% of the global burden of high-prevalent diseases. However, regulatory changes in India since 2013 have catalysed a growth in trial activity, with the number of clinical trials initiated in India by the top 20 pharma companies rising from 175 to 296 during 2020-2022. Researchers have found that 6 of the 62 completed trials and 20 of the 362 incomplete trials had planned to recruit or actually recruited 60% or

Pharma companies to adopt WHO-standard manufacturing practices for quality products

regulators to probe why some global trials had 60% or

The Union Health Minister Mansukh Mandaviya has

more participants from India.

10 PHARMA machines & technology

more participants from India. They have asked drug

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News & Updates

GLOBAL PHARMA

FDA Takes Steps to Advance the Development of Novel Therapies for Stimulant Use Disorders The FDA has published guidance to assist sponsors in developing treatments for stimulant use disorders, including perspective on development program and clinical trial design.

Drug-delivery technique for brain cancer shows growing promise A group of researchers from the University of Texas at Dallas and UT Southwestern Medical Center have developed a technique to deliver medication through the blood-brain barrier, and it has shown promise in treating glioblastoma, the most common type of brain cancer in humans. In a preclinical study published in Nature Communications, the researchers demonstrated the effectiveness of the method in mice. Glioblastoma is an aggressive form of brain cancer that affects around 12,000 people in the US every year, and patients typically have a median survival rate of 15 to 18 months after diagnosis. Current treatments, including surgery, chemotherapy, and radiation, have limited effectiveness because most medications cannot cross the blood-brain barrier. This barrier, consisting of blood vessels in the brain, acts as a filter and prevents substances from reaching the brain parenchyma. The researchers' drugdelivery method involves using gold nanoparticles targeted at the blood vessels, which are injected into the bloodstream along with the medication. By applying short laser pulses to the mouse skull, the nanoparticles are activated, temporarily permeating the blood-brain barrier and allowing the medication to reach its target. The study successfully demonstrated this approach using paclitaxel, a chemotherapy drug that does not typically cross the barrier on its own. The tumors in the mice decreased in size, and their survival rate increased by more than 50%. However, further research is necessary before the method can be tested in humans. The researchers received funding for their work from various organizations, including the Cancer Prevention & Research Institute of Texas, the Department of Defense, the National Science Foundation, the National Institutes of Health, and the American Heart Association.

12 PHARMA machines & technology

“Currently there is no FDA-approved medication for stimulant use disorder. When finalized, we hope that the guidance will support the development of novel therapies that are critically needed to address treatment gaps," said Marta Sokolowska, Ph.D., deputy center director for Substance Use and Behavioral Health in FDA's Center for Drug Evaluation and Research. “The guidance is one of the actions within the agency's Overdose Prevention Framework, which includes appropriate prescribing of prescription stimulants as well as development of evidence-based treatments for stimulant use disorder.” The draft guidance provides recommendations on how to design clinical trials to evaluate the effectiveness and safety of treatments for stimulant use disorder. It covers all aspects of the drug development process, including data collection, trial conduct, safety considerations, and new drug application requirements. Comments are welcomed within 60 days to ensure consideration by the FDA. U.S. FDA Approves Pfizer's BRAFTOVI® + MEKTOVI® for BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer The U.S. Food and Drug Administration (FDA) has approved the use of Braftovi® (encorafenib) + Mektovi® (binimetinib) in the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a specific genetic mutation called the Braf V600E mutation. This approval is based on clinical trials that demonstrated the effectiveness and safety of the combination therapy in these patients. Pfizer Inc. believes this approval is a significant step in their efforts to provide innovative and personalized medicines to patients with lung cancer. Braftovi + Mektovi is also approved for the treatment of patients with unresectable or metastatic melanoma and metastatic colorectal cancer with specific genetic mutations. Pfizer holds exclusive rights to these drugs in several regions around the world, while other companies have exclusive rights in other countries.

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News & Updates

GLOBAL PHARMA Can immunity from routine vaccines be used to fight cancer? Research being done on using immunity from routine vaccines to fight cancer Researchers from the University of Massachusetts Amherst have presented a new theory on how to battle cancer by reprogramming the body's immune system. They have shown that using a protein antigen in a childhood vaccine to target malignant tumors can effectively stop cancer from returning. In the team's theory, a non-toxic form of salmonella is used to release a drug after efficiently penetrating a solid-tumor cell. This bacterial system has the potential to be an off-the-shelf immunotherapy that could help treat a broad range of cancer patients, including those with difficult-to-treat liver, metastatic breast, and pancreatic tumors. The University of Massachusetts Amherst has filed for a patent that will be licensed to Ernest Pharmaceuticals, which was founded by the team behind the research. Their plan is to seek FDA approval for clinical trials within the next few years. Through their theory tests, the researchers have shown that their salmonella-based delivery system effectively increased survival and prevented tumor re-implantation. The team hopes to refine the treatment and ensure its safety for use in humans before starting clinical trials.

About BRAF V600E-mutant Non-Small Cell Lung Cancer (NSCLC) Lung cancer is the leading cause of cancer-related mortality worldwide, with 80-85% of cases being NSCLC. Acquired genetic abnormalities such as a BRAF V600E mutation have been linked to some types of lung cancer. Precision medicine is becoming more advanced, and recent years have seen improvements in populationlevel NSCLC mortality linked to increased use of targeted therapy and biomarker monitoring. See the complete prescribing information and medication guide for BRAFTOVI and MEKTOVI for BRAF-mt metastatic melanoma and BRAF-mt metastatic NSCLC respectively. The FDA has granted fast track designation to a dendritic cell vaccine for the treatment of glioblastoma multiforme The FDA has granted fast track designation to an autologous dendritic cell vaccine for treating glioblastoma multiforme, a type of brain cancer. This personalized immunotherapy activates the body's natural antiviral immune system to target and eliminate cancer cells in the central nervous system.

Targeting a coronavirus ion channel could yield new COVID-19 drugs One of the 29 proteins that the SARS-CoV-2 virus's genome encodes is the ion channel E. Protons and calcium ions are transported by this channel, which causes infected cells to initiate an inflammatory response that destroys tissues and exacerbates COVID-19 symptoms. Chemists at MIT have finally figured out the composition of this channel's "open" state, which permits ions to pass through. This structure may aid scientists in determining the trigger for the channel's opening and closing, in conjunction with the "closed" state structure that the same lab reported in 2020. These structures may potentially serve as a roadmap for the development of antiviral medications that block the channel and reduce inflammation. The study's primary author, Joao Medeiros-Silva, is a postdoc at MIT; it was published in Science Advances today. The paper's other authors are graduate student Noah Somberg, Aurelio Dregni, and Pu Duan, all of MIT.

14 PHARMA machines & technology

April - May 2023

Early findings indicate that patients treated with the therapy have exceeded their expected survival rates and have not reported serious adverse effects. Diakonos Oncology, the developer of the therapy, made this assertion. The treatment involves administering three injections of an autologous dendritic cell vaccine that activates the body's natural antiviral immune response to target and eliminate cancer cells in the central nervous system. The trial is being conducted at the MD Anderson Cancer Center at Cooper University Health Care and the University of Texas Health Science Center. “Because phase I clinical trials are generally not statistically powered to demonstrate efficacy, detection of a statistically significant efficacy signal is very promising,” said William Decker, Associate Professor of Immunology at Baylor College of Medicine and inventor of the DOC1021 technology.

Facts & Figures

DY K

DID YOU KNOW? The number of stroke deaths in LMICs is projected to rise sharply—widening the gap with HICs—by increasing from 5.7 million in 2020 to 8.8 million in 2050. The Indian pharmaceutical industry is the third largest pharmaceutical industry in the world by volume with a current market size of around USD 50 billion. Going forward, the industry could potentially grow to USD 120-130 billion over the next decade. The number of clinical trials initiated in India by the top 20 pharmaceutical companies increased from 175 between 2014 and 2016 to 296 from 2020 to 2022. Bowel cancer and it is the second leading cause of cancer deaths in Australians. Australians born in 1990 onwards have double the risk of developing bowel cancer compared with those born in 1950. Glioblastoma is an aggressive brain cancer that aﬀects about 12,000 people annually in the U.S Least 2.2 billion people have a near or distance vision impairment vision, impairment poses an enormous global nancial burden, with an estimated US$ 411 billion lost in workplace productivity due to poor vision. WHO launches the WHOeyes app on World Sight Day. The researchers have found that many multinational clinical trials of new medicines have recruited or planned to recruit 60 percent or more of the trial volunteers from India. Lung brosis is a debilitating disease aﬀecting nearly 250,000 people in the U.S. alone with 50,000 new cases reported each year AI is becoming increasingly pivotal in healthcare. The global AI healthcare market size will reach a staggering $31.3 billion by 2025. Adding Mounjaro to diet and exercise changes may help people lose additional weight compared to those who made just lifestyle changes alone. Indian pharmaceutical industry valued at an estimated US$42 billion in 2021 and is estimated to reach $130 billion by 2030. India is the world's largest provider of generic medicines by volume, with a 20% share of total global pharmaceutical exports. Drugs of the Future is an interdisciplinary biomedical research journal that publishes well-documented, peerreviewed articles on topics emerging from the con uence of scienti c elds including chemistry, biology, pharmacology, genomics and medicine. Baddi is home to multiple pharmaceutical companies which have established manufacturing plants and R&D hubs in the town, Asia's biggest Pharmaceuticals hub. The half-life of a drug is the time it takes for the amount of a drug's active substance in your body to reduce by half. This depends on how the body processes and gets rid of the drug. It can vary from a few hours to a few days, or sometimes weeks.

16 PHARMA machines & technology

October - November 2023

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E XC LU S I V E Quality Management

Pharma GMP & Quality Management Top Trending Drug GMP Issues By Sanjit Singh Lamba

Good Manufacturing Practices (GMP) is a system that ensures that products are systematically manufactured and controlled according to quality standards. The aim is to minimize the risks associated with pharmaceutical manufacturing that cannot be eliminated by testing the nal product. Good Manufacturing Practices (GMP) are part of a quality management system that ensures that products are systematically manufactured and controlled to quality standards that meet their intended use and market approval requirements.

18 PHARMA machines & technology

October - November 2023

Quality Management

E XC LU S I V E Dr. Sanjit Singh Lamba, Managing Partner -Trillyum Consulting and Advisory, captivated the audience at Eminences Business Media event, the cGMP Workshop 2023, with his unparalleled insights into the dynamic world of Good Manufacturing Practices (GMP). Further in response to the Pharma Machines and Technologies, he writes on the valuable insights on the most recent trends and challenges encountered by the pharmaceutical industry. But it didn't stop there; he delved deeper, providing a comprehensive understanding of the dos and don'ts through real-world case studies. Dr. Sanjit Singh Lamba Achievement-Driven Professional with cross-functional experience in diverse functions and equipped with over 33 years of pro ciency in the pharmaceutical industry. Strength in leading large teams across the globe , planning, executing & amp; spear heading all the functions right from research, manufacturing of APIs and Formulations, Quality, and business development to Sales and marketing functions with a P & L responsibility. Served at operational and leadership positions at MSD, P zer, Ranbaxy, Dabur, Gland, Lupin, Eisai etc. He pursued an MPharm, and PhD from Punjab University Chandigarh. He is the Ex MD of Eisai a Japanese pharma company. Currently, he is associated with Trillyum Consulting, Founder and Managing Partner at Chandigarh. Awarded thrice in the list of one of the “100 of the Most Inspiring People” in the life science industry by PharmaVOICE, USA. Associated with professional bodies like Indian Pharmaceutical Association, International Society for Pharmaceutical Engineers (ISPE) and serves as Past Chair – India Chapter for Parental Drug Association (PDA) and past Chairman - Technical & Supply Chain Committee for the Organization of Pharmaceutical Producers of India (OPPI) . With a patient- rst mentality and a philosophy that quality is everyone's responsibility, continue to lead to further advanced operational excellence and quality culture across the industry.

Top 5 Trending Drug GMP issues CGMP provides 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. The basic requirements for GMP are listed as follows: • Clear, written instructions and procedures • Trained operators • Records for manufacture and distribution • Proper storage and distribution • Systems for complaints and recalls.

20 PHARMA machines & technology

October - November 2023

Quality Management

E XC LU S I V E Top Trending Drug GMP issues Pharmaceuticals are subject to strict regulations due to the importance of ensuring safety, eﬀectiveness, and the signi cant impact they can have on patients' well-being. These regulations cover various aspects of pharmaceutical operations, including sales and marketing, drug price reporting, patient privacy, clinical trials, preclinical testing, and manufacturing. As a result, compliance with these regulations is a top priority for pharmaceutical companies. To ensure compliance, companies implement comprehensive good manufacturing practices and intelligence programs that involve monitoring enforcement actions by health authorities such as the FDA, including inspections, warning letters, recalls, and non-compliance reports. The pressure to comply with current good manufacturing practices (CGMP) in the pharmaceutical industry has never been higher. In scal year 2022, the US FDA issued 62 warning letters and 23 import alerts to drug organizations, underscoring the importance of adhering to regulations. It is crucial to note that the FDA constantly updates its inspection priorities, focusing on emerging issues and risks. Consequently, the speci c reasons behind FDA 483 observations may change over time. Pharmaceutical manufacturers can mitigate the risk of receiving such observations by fostering a culture of quality, adhering to GMP requirements, and staying up to date with the latest FDA guidance and regulations. Regular training and robust quality systems are vital for preventing compliance issues, improving product quality, and ensuring patient safety. Instead of waiting for an inspection failure, pharmaceutical companies should prioritize compliance with current good manufacturing practices (CGMP) for quality.

Pharmaceutical companies often face growing pressures as they approach market approval. However, it is crucial to prioritize compliance with CGMP regulations before receiving a warning. It may seem that your processes are satisfactory until an FDA inspector uncovers overlooked issues, such as unreviewed maintenance records during the absence of the lab manager. Understanding the most common compliance issues in the pharmaceutical industry is one way to avoid receiving a 483 so you can focus on those issues instead of receiving one. The top issues in the last few years are more or less the same, but the following areas have been the most prevalent in the last ve years:

22 PHARMA machines & technology

October - November 2023

Quality Management

E XC LU S I V E CITATION

SHORT DESCRIPTION

Total Form 483s issued using FDA tools for Drug Inspection

2013

2014

2015

2016

2017

2018

2019

690

645

678

691

694

716

779

§211.22(d)

Procedures applicable to the quality unit shall be in writing and shall be followed

168

148

165

153

185

208

215

§211.192

Investigations of discrepancies

239

209

250

227

278

183

167

§211.42(c)

Facilities shall include de ned areas of suﬃcient size

125

235

227

148

134

156

§211.160(b)

Lab controls should include scienti cally sound speci cations

199

165

246

133

207

209

145

§211.166(a)

Stability testing

104

126

124

111

135

§211.100(a)

Production and process controls shall be supported by written procedures

135

107

123

110

116

102

129

§211.67(b)

Equipment cleaning and maintenance

102

112

124

§211.188

Master production and control records

114

110

100

208

123

§211.113(b)

Control of microbiological contamination

119

109

157

110

121

§211.25(a)

Personnel quali cations

132

115

119

113

§211.67(a)

Equipment shall be cleaned/sanitized or sterilized

113

§211.110(a)

Sampling and testing of in-process materials and nal product

§211.165(a)

Appropriate lab tests shall be used to determine conformance to speci cations

§211.68(a)

Automatic, mechanical, and electronic equipment

§211.100(b)

Contemporaneous documentation of activities

1. Absence of written procedures or failure to follow written procedures The FDA issued 161 citations in 2022 for procedures that were not in writing or were not followed completely. Implementing, deploying, and maintaining a quality management system requires easy-to-understand procedures and work instructions. According to the FDA Code of Federal Regulations, pharmaceutical companies must create written

24 PHARMA machines & technology

21 CFR 211.22(d) "The responsibilities and procedures applicable to the quality control unit are not in writing or fully followed.” 21 CFR 211.100(a) “There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.”

October - November 2023

Quality Management

E XC LU S I V E standard operating procedures (SOPs) for production and process control. These SOPs must include all requirements for drug identity, strength, quality, and purity. Operational and quality control units should review and approve SOPs. Whenever operations diverge from these SOPs, organizations must document compliance and create a record with a clear justi cation. 483 observations issued for CFR 211.100 in a recent year are often attributed to management and training issues, along with noncompliance or inadequate SOPs. Excerpts from 483 letters have included the following language: • There are no written procedures in place at your rm • Documented instances of non-compliance with SOPs exist

a report that includes conclusions and follow-up actions when there is a discrepancy or failure. Red ags include: • There is no clear understanding of the root causes • It is common to identify root causes as "human mistakes" or similar shallow explanations • As a result of improper categorization, the root causes are unrelated to the observations. • Signs that someone isn't reading what they're signing • Inappropriate use of investigation tools There are a variety of ways that organizations can become non-compliant with CFR 211.192, including: • The failure to review all logs • Logs of downtime, cleaning, and clearance should all be reviewed

• Procedures were not approved by your rm's quality control unit

• Failures in the procedure

• Documentation of SOP revisions is inadequate

• It is not possible for laboratory workers to review their own work or batch records

• SOPs have no records of cGMP training • The GM and Production Supervisor both stated that they were unaware of the SOP • Despite the fact that your SOP is in English, one operator cannot read it. With better transparency and work ows, such as the Lab Information Management system and other documentation software work ows, many of these issues can be resolved. 2. Faulty production record reviews and Inadequate Investigations 21 CFR 211.192 "There is a failure to thoroughly review any unexplained discrepancy or the failure of a batch or any of its components to meet any of its speciﬁcations, whether or not the batch has been already distributed.” In 2022, 104 pharmaceutical companies did not meet standards for investigating discrepancies and failures. Pharma QC must review and approve all drug production and control records, including packaging and labelling records, to determine compliance with standard operating procedures. The QC is responsible for conducting a thorough investigation and creating

26 PHARMA machines & technology

• Procedures are not shared • QC and operations should have a uni ed set of standards and SOP for batch record review to avoid confusion. 3. Failures in laboratory controls 21 CFR 211.160(b) “Laboratory controls do not include the establishment of scientiﬁcally sound and appropriate speciﬁcations, standards, sampling plans or test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling or drug products conform to appropriate standards of identity, strength, quality, and purity." Last year, pharmaceutical companies received 78 citations for not having scienti cally sound laboratory controls. Scienti cally sound laboratory controls ensure accurate, reliable lab results. Sound lab controls comply with cGMP in the following ways: • Scienti cally sound and appropriate speci cations, standards, and test procedures • Monitoring the reliability, accuracy, precision, and performance of test procedures and instruments

October - November 2023

Quality Management

E XC LU S I V E • Identi cation and handling of test samples

noncompliance:

An FDA laboratory inspection focuses on both lab operations and raw data to determine whether a pharma organization is compliant with cGMP. You can expect an inspector to look at:

• On loose paper, maintenance activities have been logged as needed.

• Lab records and logs • SOPs

• After cleaning tasks were completed, cleaning records were not reviewed and approved.

• Analytical procedures

For each maintenance activity, technicians were not instructed to record data in SOPs.

• Raw lab data • Lab equipment Procedures, raw data, and management records are all necessary evidence for quality-driven operations. Establishing scienti cally sound lab procedures is an enormous responsibility. In addition to instrument calibration, employee compliance with SOPs, and management investigations to determine the root cause of operations, raw data can reveal a lot about compliance and management. 4. Inadequate cleaning, sanitizing, and maintenance 21 CFR 211.67(a) “Equipment and utensils are not cleaned, maintained, or sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product.” In 2022, the FDA slapped the wrists of 50 drug companies for poor cleaning. Essentially, if your company makes medicine, then the FDA wants to make sure that you're working in a clean, sanitized environment to prevent malfunctions or contamination. For cleaning and maintenance, SOPs should be followed, including: • Cleaning responsibilities • Schedules for maintenance and cleaning • A detailed description of the methods to be used • Contamination prevention for clean equipment • Before using equipment, inspect it for cleanliness • Keeping records of maintenance, cleaning, sanitizing, and inspection An analysis of 483 observations for 21 CFR 211.67(a) in one recent year revealed the following reasons for

28 PHARMA machines & technology

• Forty-three of approximately 55 maintenance records were not signed by the responsible employee.

There have been 483 observations within this category resulting from visible maintenance or cleaning issues. There have been reports of out-oforder equipment, holes in the ceiling of the laboratory or rust that could threaten the cleanliness of the facility. In order to prevent contamination and protect drug quality, SOPs must be reviewed frequently. 5. Control of master formula records by computer 21 CFR 211.68(b) “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.” There were 56 violations of this rule in 2022, according to the FDA. It is possible for your critical records to be compromised when documents are not protected from unauthorized edits. Keeping track of changes and approving edits within quality management system software can prevent that and help companies comply with this regulation. It can also provide clear audit trails for FDA inspections, showing who changed what and when. Form 483s can also be caused by: • The degree and frequency of input/output veri cation is determined by the "complexity and reliability of the computer or related system" according to 21 CFR 211.68(b). • Data backups are required by the FDA except in certain cases where automation is being used, in which case a written record and validation data are required.

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Quality Management

E XC LU S I V E Robust Root Cause Analysis Methods During the process of conducting root cause analysis in pharmaceutical manufacturing, it is crucial to take into account the speci c type of issue, available data, and potential hazards to the quality of the product and safety of the patients. To ensure a comprehensive and eﬃcient investigation, cross-functional teams collaborate. Additionally, maintaining regulatory compliance requires documenting and tracing the analysis process and implementing corrective and

preventive actions (CAPA). Robust methods of root cause analysis play a vital role in identifying the root cause of failures in pharmaceutical manufacturing and implementing effective CAPAs. Various well-established methods and tools are utilized in the pharmaceutical industry as standard methods for conducting root cause analysis. 1. Ishikawa (Fishbone) Diagram: The Ishikawa or shbone diagram is an effective tool for identifying potential causes of issues by categorizing factors like people, equipment, materials, processes, and environment. This helps in identifying the root cause of the problem in a structured manner. 2. 5 Whys Technique: A simple yet powerful method of asking "why" several times, usually ve, to understand the root cause of a problem. This approach encourages a deeper understanding and examination of problems. 3. The Failure Mode and Effects Analysis (FMEA): A systematic approach that evaluates the probability and severity of potential failures in a process. This helps in prioritizing which problems to address rst and is commonly used to prevent failures proactively. 4. Fault Tree Analysis (FTA): FTA is employed to study the various factors that may contribute to a speci c event of failure. This technique involves creating a tree-like diagram that depicts the logical connections among the root causes and the ultimate failure. 5. Bowtie Analysis: Similar to FTA and is employed to assess and visualize the chain of causes and effects of an event. This technique is particularly helpful in risk assessment and the implementation of effective risk controls. 6. Pareto Analysis: The Pareto principle, which states that 80% of problems arise from 20% of the root causes. Pareto Analysis helps to identify the most signi cant contributors, prioritize issues and enables the organization to focus on the most impactful issues. 7. Root Cause Analysis (RCA): RCA software tools are designed for analyzing the root cause of problems. These tools feature templates, work ows, and data

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Quality Management

E XC LU S I V E analysis capabilities that streamline the investigation process. 8. Statistical Methods: Statistical techniques like Regression Analysis, Design of Experiments (DOE), and Hypothesis Testing can be useful in identifying root causes when relevant data is available. 9. Fault Detection and Analysis (FDA) tools: These tools use real-time data from manufacturing processes to detect and analyze deviations and anomalies. They can help identify root causes in near-real-time, allowing for immediate corrective actions. 10. Change Analysis: this tools and methodologies are employed to assess the impact of process changes on product quality and identify any

potential associated issues when investigating failures related to process changes. 11. Human Error Analysis Tools: When human error is a potential root cause, Human Error Analysis tools like the Human Error Assessment and Reduction Technique (HEART) or the Systematic Human Error Reduction and Prediction Approach (SHERPA) can be applied to understand and prevent errors. 12. The Failure Reporting, Analysis, and Corrective Action System (FRACAS): A structured approach used to collect data on failures, analyse the data to identify root causes and implement corrective actions. This approach is commonly utilized in industries such as aerospace and defence and can be adapted for pharmaceutical manufacturing.

Pressure from Leadership Leadership is a constantly evolving and dynamic journey. To thrive in today's fast-paced and complex business environment, leaders must be willing to let go of old habits, acquire new skills, and consistently demonstrate eﬀective leadership behaviours. Eﬀective leadership is an ongoing process of growth and development. Leaders should embrace the idea of unlearning, learning, and implementing new skills and behaviours in order to adapt to changing circumstances and be more successful in their roles. Here are some key areas that leaders should focus on when it comes to unlearning, learning, and practicing: Unlearn

Learn

Practice

1. Micromanagement: Instead of micromanaging their team members, leaders should learn to empower their teams and trust them to carry out tasks and make decisions.

1. Emotional Intelligence (EQ): It is essential for eﬀective leadership to develop emotional intelligence (EQ). Leaders must acquire the skills to understand and manage their own emotions as well as those of their team members. This fosters collaboration and empathy.

1. Lead by Example: Practice what you preach. Leaders should model the behavior and values they expect from their team members. This builds trust and credibility.

2. Command-and-Control Leadership: To create a more collaborative and inclusive environment, leaders may need to abandon traditional command-and-control leadership styles and encourage input and feedback from team members. 3. Resistance to Change: Leaders should embrace a more agile and adaptable mindset by letting go of their resistance to change. Change is inevitable,

32 PHARMA machines & technology

2. Continuous Learning: Make learning a regular practice. Stay updated on industry trends, 2. Adaptive Leadership: In rapidly leadership theories, and new changing environments, leaders technologies that can impact need to be adaptable. They your eld. should learn how to adjust their 3. Feedback and Coaching: leadership style according to Regularly provide feedback and diﬀerent situations and coaching to team members to challenges. This includes help them grow and develop eﬀectively leading through their skills. Also, be open to uncertainty and ambiguity. receiving feedback and acting upon it.

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Quality Management

E XC LU S I V E Unlearn

Learn

Practice

and being exible and open to new ideas and approaches is crucial.

3. Eﬀective Communication: It is crucial for leaders as they should continuously improve their communication skills, which involve active listening, clearly articulating ideas, and providing constructive feedback.

4. Delegation: Practice eﬀective delegation by assigning tasks and responsibilities to team members based on their strengths and abilities. Trust them to deliver results.

4. Over-reliance on Hierarchies: In today's organizations, hierarchies are becoming atter. Leaders should unlearn the notion that leadership is solely based on one's position and instead embrace the idea that leadership can emerge from any level of the organization. 5. Blame Culture: Instead of fostering a culture of blame, leaders should focus on promoting a culture of accountability where mistakes are seen as opportunities for learning and improvement.

4. Con ict Resolution: Leaders can manage and resolve con icts within their teams by learning eﬀective con ict resolution techniques. This leads to healthier working relationships. 5. Innovation and Creativity: Leaders should encourage innovation and creativity within their teams. They should create an environment that welcomes new ideas and approaches to problem-solving.

Effective Communication Effective communication is crucial for the success of any organization, as it promotes teamwork, understanding, and cohesion among team members. Enhancing communication within a team or organization is an ongoing process that requires commitment, attentiveness, and a proactive approach to addressing any communication issues that arise. By implementing these strategies and fostering a culture of effective communication, you can greatly minimize communication challenges and improve collaboration and productivity. Tackling communication issues involves adopting practices and strategies to enhance communication at all levels. Here are some steps to implement effective communication: 1. Establish Clear Communication Goals and Objectives: • De ne clear and speci c communication goals for your team or organization. • Determine what information needs to be

34 PHARMA machines & technology

5. Empowerment: Empower team members to make decisions and take ownership of their work. Encourage autonomy and provide support when needed. 6. Ethical Leadership: Practice ethical leadership by making ethical decisions, promoting ethical behaviour in the workplace, and being a role model for ethical conduct. 7. Crisis Management: Develop and practice crisis management skills to eﬀectively navigate and lead during challenging times.

communicated, to whom, and why it's important. 2. Create a Communication Plan: • Develop a structured communication plan that outlines the key messages, channels, and timelines for communication. • Ensure that the plan addresses both internal and external communication needs. 3. Use Multiple Communication Channels: • Recognize that different team members may prefer different communication methods (e.g., email, inperson meetings, video conferences, messaging apps). • Utilize a mix of channels to reach a diverse audience effectively. 4. Open and Transparent Communication: • Foster a culture of transparency where information is shared openly, and team members feel comfortable expressing their thoughts and concerns. • Share both good news and challenges with the team.

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Quality Management

E XC LU S I V E 5. Active Listening: • Encourage active listening by providing opportunities for team members to express their opinions and ask questions. • Listen attentively without interrupting, and ask clarifying questions to ensure understanding.

• Leaders should be approachable and willing to engage in open dialogue with team members. 13. Celebrate Achievements: • Celebrate team achievements and milestones to foster a positive and motivating atmosphere.

6. Clear and Concise Messages:

• Use these moments to communicate the team's progress and future goals.

• Communicate messages in a clear, concise, and easily understandable manner.

14. Adapt and Evolve:

• Avoid using jargon or technical terms that team members may not be familiar with. 7. Feedback Mechanisms: • Establish feedback mechanisms, such as regular check-ins, surveys, or suggestion boxes, to gather input and opinions from team members. • Act on feedback and communicate the actions taken in response. 8. Training and Development: • Provide communication training and resources to team members to improve their communication skills. • Offer workshops or coaching on effective communication techniques. 9. Regular Meetings and Updates: • Schedule regular team meetings, one-on-one discussions, or departmental updates to keep everyone informed and engaged. • Stick to the schedule to ensure consistency. 10. Technology Tools: • Leverage communication and collaboration tools and software (e.g., Slack, Microsoft Teams, project management software) to facilitate efficient and real-time communication. 11. Respect Diverse Perspectives: • Acknowledge and respect diverse perspectives, backgrounds, and communication styles within the team. • Encourage inclusivity and ensure that all voices are heard. 12. Leadership Role Modelling: • Leaders should set an example by demonstrating effective communication behaviours.

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• Continuously assess the eﬀectiveness of your communication strategies. • Be willing to adapt and re ne your communication practices based on feedback and changing needs.

Statistical Process Control Statistical process control (SPC) is a methodology utilized in manufacturing to eﬀectively monitor and regulate processes to ensure quality. It involves the use of statistical techniques to measure and analyse process performance, detect variations, and make data-driven decisions to maintain consistency and quality of products. SPC is especially crucial in the pharmaceutical industry, where the utmost importance is placed on product quality and patient safety. In order to apply statistical process control appropriately in pharmaceutical manufacturing, a combination of statistical expertise, eﬀective data management, and a commitment to quality is necessary. When implemented correctly, SPC can assist pharmaceutical companies in maintaining consistent product quality, minimizing waste and rework, and ultimately safeguarding patient safety. It is imperative to have trained personnel who possess a deep understanding of SPC principles and are equipped with the ability to accurately apply them within the manufacturing environment. Here's how to use SPC appropriately in pharmaceutical manufacturing: 1. Identify Critical Quality Attributes (CQAs) and Critical Process Parameters (CPPs): • Determine the critical quality attributes (CQAs) of the pharmaceutical product. These are the characteristics that must be controlled within prede ned limits to ensure the product meets its intended speci cations.

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Quality Management

E XC LU S I V E • CPPs are the variables in the manufacturing process that can have a signi cant impact on product quality. 2. Collect data: · Establish a data collection plan to collect relevant data from the manufacturing process. This can include measurements of temperature, pressure, ow rates, pH levels, and other data. · Use appropriate instruments and measurement techniques to ensure consistent and accurate data collection. 3. Establish a control chart: • X-bar charts and R-charts are commonly used for continuous data, and p-charts and np-charts for discrete data. •· The control limits are calculated using historical data or statistical methods and represent the range within which the process should operate to produce consistently high-quality products. 4. Monitor the Process: • Continually monitor the manufacturing process using the control charts. Chart data points as they are collected. • Analyse trends, patterns, and deviations from the control limits. These can indicate variations in the process. 5. Respond to out-of-control situations: • An out-of-control condition occurs when data points fall outside the control limits or show nonrandom patterns. • Determine whether the variation is due to common causes (inherent to the process) or special causes (unusual events).

about the status of the process and any signi cant deviations from the expected results. 7. Continuous Improvement: • Using the data collected over time, analyse trends and make improvements to the process. Continuous improvement is an important aspect of statistical process control. • To minimize the occurrence of out-of-control conditions and variations, implement preventive actions. 8. Observance of regulations: • In the pharmaceutical industry, compliance with regulatory requirements, such as those set by the FDA, EMA, and other relevant authorities, is essential to maintaining product quality and safety.

Developing Speci cations Developing scienti cally robust speci cations for laboratory controls in the pharmaceutical industry is crucial for ensuring the quality and safety of pharmaceutical products. These speci cations outline the acceptable limits and criteria that raw materials, intermediate products, and nished products must adhere to. To guide the development of such speci cations, here is a systematic approach that follows a scienti cally sound process. Understand Regulatory Requirements: Familiarize yourself with the regulatory requirements speci c to your region, such as those provided by the CDSCO in India or FDA (United States) or the European Medicines Agency (EMA). Regulations often provide guidance on establishing speci cations. Identify Critical Quality Attributes (CQAs):

• The process can be brought back under control by making appropriate corrections, such as adjusting parameters, recalibrating equipment, or making other necessary changes.

Determine the critical quality attributes (CQAs) of the pharmaceutical product. CQAs are the physical, chemical, biological, or microbiological characteristics that must be controlled to ensure product quality and safety. This is a crucial step in speci cation development.

6. Documents and Reports:

Review Available Data:

• Keep comprehensive records of all data collected, including control charts, investigation reports, and corrective actions.

Collect and review historical data, including data from process development, stability studies, and prior manufacturing batches. This data can provide insights into the variability and trends associated with the

• Make sure all relevant stakeholders are informed

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Quality Management

E XC LU S I V E product and its components.

Documentation and Justi cation:

Select Analytical Methods:

Document the rationale behind each speci cation and the scienti c basis for its establishment. This documentation is crucial for regulatory compliance and transparency.

Choose appropriate analytical methods to test and measure the identi ed CQAs. These methods should be validated and capable of providing accurate and precise results. Establish Acceptance Criteria: De ne acceptance criteria for each CQA based on scienti c principles, risk assessments, and regulatory guidelines. Acceptance criteria should consider the intended use of the product and potential patient safety concerns. Consider Variability and Clinical Impact: Assess the variability of CQAs and determine their clinical impact. This involves understanding how variations in CQAs can affect the safety and efficacy of the product. Use Risk Assessment Tools: Consider using risk assessment tools, such as Failure Mode and Effects Analysis (FMEA) or Quality Risk Management (QRM), to evaluate the impact of variations in CQAs on product quality. Set Realistic and Achievable Limits: Specify limits that are achievable based on the available analytical methods and technology. Avoid setting overly stringent limits that cannot be consistently met. Account for Manufacturing Process Changes: Anticipate potential changes in the manufacturing process and how they might impact CQAs. Speci cations should be exible enough to accommodate process adjustments without compromising product quality. Consider Stability Data: Use stability data to establish shelf-life speci cations for the product. Stability studies help determine how the product's quality attributes change over time under various storage conditions. Statistical Tools and Data Analysis: Utilize statistical tools, such as statistical process control (SPC) charts and trend analysis, to analyze data and set appropriate speci cations.

40 PHARMA machines & technology

Review and Approval: Ensure that speci cations are reviewed and approved by a cross-functional team, including experts in formulation, analytical chemistry, quality assurance, and regulatory aﬀairs. Periodic Review and Update: Regularly review and, if necessary, update speci cations as new data becomes available or as manufacturing processes evolve. Compliance with Regulations: Ensure that speci cations are in compliance with relevant regulations and guidelines and that they meet the expectations of regulatory authorities. Developing scienti cally sound speci cations is a complex and iterative process that requires a multidisciplinary approach and collaboration between various departments within a pharmaceutical company. Continuous monitoring and improvement of speci cations are essential to maintaining product quality and ensuring patient safety throughout the product's life cycle.

Sampling Plans and Testing Methods Sampling plans and testing methods play a crucial role in ensuring the quality control of pharmaceutical manufacturing. Problems in these areas can have signi cant consequences, including compromised product quality, failure to meet regulatory requirements, and potential harm to patients. The following are some common issues that arise in relation to sampling plans and testing methods in pharmaceutical manufacturing: 1. Insuﬃcient Sampling Frequency: Sampling too infrequently may result in the failure to detect sporadic or intermittent quality issues. On the other hand, excessive sampling can lead to resource ineﬃciency. 2. Inconsistent Sampling Procedures: Variability in

October - November 2023

Quality Management

E XC LU S I V E how samples are collected or handled can introduce bias or errors into the sampling process. Standardized procedures and training are crucial. 3. Small Sample Sizes: Small sample sizes may not accurately represent the variability within a batch, potentially leading to false acceptance of nonconforming products. 4. Large Sample Sizes: Conversely, excessively large sample sizes can be time-consuming and costly, especially for expensive or time-sensitive products. 5. Unrepresentative Sampling: Failure to select samples that accurately represent the entire batch can lead to misleading results. It is important to consider techniques such as strati ed sampling and randomization. 6. Improper Storage and Handling: Mishandling of samples, such as improper storage conditions, can cause degradation or contamination, which can aﬀect test results. 7. Sampling Bias: Bias in sample selection can occur if certain parts of a batch are favoured or avoided during the sampling process. This can potentially result in inaccurate assessments of product quality. Testing Method Issues: 1. Outdated Methods: Using outdated or inappropriate testing methods can result in inaccurate results and potential non-compliance with evolving regulatory requirements. 2. Method Validation and Veri cation: Failure to properly validate and verify testing methods for accuracy, precision, speci city, and sensitivity can lead to unreliable results. 3. Inadequate Training: Insuﬃcient training of laboratory personnel can cause errors during testing, misinterpretation of results, and inconsistent reporting. 4. Instrument Calibration and Maintenance: Neglecting the calibration and maintenance of analytical instruments can result in inaccurate measurements and unreliable testing. 5. Method Transfer Issues: When transferring testing methods between locations or instruments, discrepancies or variations in results can occur if not managed properly.

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6. Data Integrity: Insuﬃcient controls and procedures can lead to data integrity issues, such as incomplete or manipulated data, compromising the accuracy and integrity of test results. 7. Stability of Reagents and Standards: The stability of reagents and standards used in testing is crucial. If these materials degrade or are mishandled, it can impact the reliability of test results. 8. Interference and Cross-Contamination: Contamination or interference from other substances or samples can result in inaccurate results. Proper cleaning and handling procedures are vital. 9. Inadequate Method Transfer: Discrepancies in equipment, environment, or personnel training when transferring methods between laboratories or manufacturers can aﬀect the reliability of the method. 10. Regulatory Compliance: Failure to keep up with evolving regulatory requirements and guidelines for testing methods can lead to non-compliance and potential regulatory issues. In order to tackle these problems, pharmaceutical manufacturers need to invest in strong quality control systems. This includes implementing thorough sampling plans and validated testing methods. It is crucial to continuously train, calibrate, and monitor these processes to ensure their reliability and accuracy. Collaboration between quality control, manufacturing, and research and development teams is essential for resolving issues and enhancing the overall quality of the products.

Written Procedures for Production and Process Controls As established in 21 CFR 211.100(a) by the United States Food and Drug Administration (FDA), written procedures in manufacturing and process control are crucial for maintaining the quality, safety, and consistency of pharmaceutical goods. Common faults with these documented processes might cause compliance and quality concerns. Here are some typical concerns and solutions to them: Common Issues: 1. Outdated Procedures: Because of changes in equipment, processes, legislation, or best practises, procedures may become obsolete.

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Quality Management

E XC LU S I V E 2. Incomplete or Inaccurate Procedures: Written procedures may be missing important elements, include errors, or omit vital phases. 3. Noncompliance with Current Regulations: Procedures may not be in accordance with current regulatory requirements or industry standards. 4. Failure to Manage Versions of Written Procedures: Failure to manage versions of written procedures might result in personnel utilising obsolete materials. 5. Ineffective Change Control: Changes to processes may not be effectively recorded, evaluated, or authorised, resulting in confusion and possible compliance difficulties. 6. Poorly Communicated processes: Employees may be unaware of, or lack access to, the most recent processes, limiting their ability to follow them correctly. How to Resolve These Issues: 1. Regular Review and Update: Implement a thorough procedure review and update process. Assign responsibilities for routine evaluations and ensure that procedures adhere to the most recent requirements and best practices. 2. Document Control: Set up a document control system to keep track of different versions of written procedures. Procedures should be clearly labeled and dated to show their status. 3. SOP Training: Make certain that staff receive thorough training on standard operating procedures (SOPs) and have access to the most recent versions. 4. Change Management: Create a systematic change management process for examining, approving, and documenting procedure modi cations. This procedure should include all essential parties. 5. Cross-functional collaboration: Encourage collaboration between production, quality control, and quality assurance teams to ensure that processes are correct and effective. 6. Validation and Veri cation: Validate and verify procedures through testing and inspection to ensure they function as intended. This is especially signi cant for vital procedures.

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7. In accordance with Audits: Conduct frequent internal audits to ensure that documented processes are in accordance with current rules and industry standards. 8. Employee feedback: Encourage workers to submit input on the usefulness and clarity of procedures. Consider their feedback while rewriting and updating documents. 9. Training Records: Keep records of staﬀ procedures training to ensure that everyone is utilising the most recent versions. 10. Risk Assessment: Identify and reduce possible hazards associated with procedures using risk assessment methods such as Failure Mode and Eﬀects Analysis (FMEA). 11. Regulatory Guidance: Keep up to speed on changes in regulations and guidance papers pertaining to documented processes, and integrate adjustments as appropriate. 12. Continuous Improvement: Foster a culture of continuous improvement by utilising feedback and lessons acquired from deviations and nonconformances to improve procedures and processes. A methodical and forward-thinking strategy is necessary to resolve problems related to written procedures in production and process control. This approach involves tackling these issues head-on by verifying the precise, current, and regulatorycompliant nature of the procedures in question. By doing so, pharmaceutical manufacturers can ensure the quality, safety, and regulatory adherence of their products.

Unlearn, Learn and Relearn Unlearn: 1. Change Resistance: Unlearn change resistance and embrace an adaptation culture. To remain compliant and competitive, the sector must be prepared to adapt procedures, adopt new technology, and update practises. 2. Departmental Isolation and Silos: Break down departmental silos and promote cross-functional communication. Quality and compliance are the responsibility of everyone, not only those involved in regulatory aﬀairs or quality control.

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Quality Management

E XC LU S I V E 3. Compliance as a Barrier: Dispel the belief that compliance is a barrier to innovation. Consider compliance to be the cornerstone for innovation and product quality. 4. Overdependence on Paper-Based methods: Unlearn your dependency on paper-based documentation methods. To enhance accuracy and traceability, migrate to electronic records and data management systems. Learn: 1. Data Analytics and Arti cial Intelligence: Discover how to use data analytics and arti cial intelligence (AI) to improve quality control and compliance. These technologies can detect patterns, abnormalities, and possible problems more quickly and eﬃciently than human techniques. 2. Risk-Based methodologies: Learn and apply riskbased quality and compliance methodologies. Concentrate resources on high-risk areas, enabling for more eﬃcient and focused compliance activities. 3. Ongoing Improvement: Adopt continuous improvement concepts (e.g., Lean, Six Sigma) to optimize operations, decrease waste, and increase quality. Learning problem-solving strategies and process optimization methodologies is required. 4. Supply Chain Visibility: Discover how to improve supply chain visibility and traceability, assuring raw material and component integrity across the supply chain. Relearn: 1. Regulatory Updates: Relearn and stay up to date on changes in regulatory standards. Regulations are changing, and businesses must adapt to be compliant. 2. Cybersecurity Awareness: Refresh and enhance your cybersecurity knowledge. As processes become more digital, securing data and systems from cyberattacks is critical for compliance and product safety. 3. Patient-Cantered Approach: Remind yourself of the signi cance of a patient-centred approach. While adhering to legal requirements, the sector must prioritize patient safety and satisfaction. 4. Environmental Sustainability: Relearn and rethink environmental sustainability practices.

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Consider the environmental eﬀect of pharmaceutical production and look for solutions to reduce it. 5. Human Factors Engineering: Recalibrate your understanding of the importance of human factors engineering in product design and production processes. Human factors can have a big in uence on product quality and patient safety. 6. Quality Culture: Continually relearn the importance of a strong quality culture. Quality should not be an afterthought but integrated into every aspect of the organization's operations. 7. Adaptive Quality Management Systems: Remind yourself of the need of adaptive quality management systems that can swiftly adjust to changes in the industry and regulatory landscape. Because of advances in science, technology, and regulatory requirements, the pharmaceutical sector is continually developing. Organisations must be adaptive, responsive to change, and committed to a culture of learning and continuous development in order to increase quality and compliance. Pharmaceutical rms may eﬀectively ful l the demands of a dynamic and tightly regulated market by rejecting outmoded practises, adopting new skills and techniques, and strengthening the principles of quality and compliance.

Enhancing the Culture of Quality It is crucial to enhance the culture of quality in the pharmaceutical industry to guarantee the safety, eﬀectiveness, and adherence of pharmaceutical products. Achieving a robust quality culture necessitates dedication, strong leadership, and a continuous improvement mind set. Here are the steps to enhance the culture of quality in the pharmaceutical industry: 1. Leadership commitment: Senior leaders need to actively demonstrate their dedication to quality. This commitment should be communicated consistently throughout the organization. 2. Clarify quality values and expectations: Clearly de ne the values and expectations regarding quality in a quality policy or mission statement. Ensure that these principles align with the overall goals and mission of the organization.

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Quality Management

E XC LU S I V E 3. Education and training: Provide comprehensive education and training on quality principles and practices to all employees, from top management to frontline staﬀ. This training should cover regulatory requirements, standard operating procedures (SOPs), and good manufacturing practices (GMPs). 4. Empower employees: Encourage employees to take ownership of quality by empowering them. Foster an environment where they feel comfortable identifying and reporting any quality issues, near misses, or opportunities for improvement. Establish a culture where employees can voice concerns and make suggestions for enhancing quality.

to identify trends and areas for improvement. 9. Documented procedures: Ensure that all procedures and processes are well-documented and in compliance with regulatory standards. Emphasize the importance of consistently following established procedures. 10. Auditing and inspection: Conduct regular internal audits and inspections to assess compliance with quality standards and identify areas for improvement. Be prepared for external regulatory inspections by maintaining an inspection-ready state. 11. Quality risk management: Implement quality risk management processes to assess and mitigate risks to product quality and patient safety. Utilize risk assessments to prioritize quality-related activities.

5. Foster cross-functional collaboration: Encourage collaboration and cooperation between diﬀerent departments, such as research and development, manufacturing, and quality control. This collaborative approach ensures that quality considerations are integrated throughout the entire product lifecycle. Encourage interdisciplinary teams to address complex quality challenges.

12. Open communication: Encourage open and transparent communication at all levels of the organization. Share information on quality performance and achievements. Establish regular channels for employees to provide feedback and express concerns.

6. Continuous improvement: Implement continuous improvement methodologies like lean or Six Sigma to identify and eliminate waste, ineﬃciencies, and sources of defects in processes. Actively involve employees in improvement initiatives.

13. Recognition and reward: Recognize and reward individuals and teams for their contributions to quality improvements and adherence to quality standards. Utilize positive reinforcement to promote a culture of quality.

7. Root cause analysis: Promote the use of root cause analysis techniques to identify the underlying causes of quality issues and prevent their recurrence. Make sure that corrective and preventive actions (CAPAs) are implemented eﬀectively.

14. Regulatory compliance: Maintain a strong focus on regulatory compliance. Stay updated with evolving regulations and ensure that processes and products meet or exceed regulatory requirements.

8. Measurement and metrics: Establish key performance indicators (KPIs) and metrics related to quality. Regularly monitor and report on these metrics to track progress. Utilize data-driven decision-making

15. Patient-centric approach: Prioritize patient safety and well-being in all quality-related decisions and actions. Remember that the ultimate goal is to provide safe and eﬀective pharmaceutical products to patients.

Enhancing the culture of quality is an ongoing eﬀort that requires commitment and vigilance at all levels of the organization. It should be woven into the fabric of the company's operations and become an integral part of the organizational identity. Over time, a strong quality culture not only ensures regulatory compliance but also fosters trust and con dence in the pharmaceutical industry and its products. References: Inspection Observations | FDA Top 10 GMP Audit Citations: FDA & TGA Inspections (onlinegmptraining.com) FDA ﬁnds most basic GMP quality control and quality assurance violations - GMP Journal (gmp-journal.com) FDA Warning Letter & Inspection Observation Trends [Updated 2023] (thefdagroup.com)

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Tablet Tooling

A R T I C L E

INCREASE TABLET PRODUCTION A De nitive Guide to MULTI-TIP TOOLING

By Kevin Queensen

To increase production and minimize downtime cost-eﬀectively and eﬃciently, multi-tip tooling is the way to go. Although it may be seen as modern, multi-tip tools have actually been used since tablet presses emerged. Single-station presses used to dominate production, yet they could not keep up with the growing demand due to their limited tooling stations. Multi-tip tools were then developed to increase production and reduce labour, maintenance, energy, and oor space expenses. The introduction of the 16-station rotary presses in the late 1800s reduced the popularity of multi-tip tools as they could cope with the demand at the time. However, due to the increasing demand for products in various tableting sectors, including pharmaceutical, OTC, nutraceutical, confectionary, and industrial, multi-tip tools are now seeing a resurgence in usage to meet the needs of manufacturers.

Multi-tip Tooling Types There are two types of multi-tip tooling: assembled type (tips, caps, and bodies manufactured as individual parts then assembled) and solid type (multiple tips are machined from a solid steel blank). Each has advantages and disadvantages, which should be considered when evaluating a product for multi-tip tooling.

Assembled type punch

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Solid type punch

Mechtek

Tablet Tooling

A R T I C L E Assembled type

Solid Type

+ Damaged, and/or worn tips can be replaced. + Punch body can be designed to be universal. + Materials can be optimized for individual components. + May allow for more tips.

+ No assembly required. + No mating parts with crevices. + Easier to clean and maintain. + May allow for more tips. + May allow for larger tips. + More robust design

- Diﬃcult to maintain and clean. - Potential for product or cleaning solutions to migrate into mating part crevices. - Requires skilled technicians to disassemble, clean, and reassemble.

Assembled Type The assembled type of multi-tip punch is most often used for mini/micro tabs (4mm and smaller diameter) as micro tabs have found increasing use in time release, veterinary, pediatric, and geriatric dosage forms.

Damage to any tip may scrap the entire punch. Worn tips require a new entire punch. Cannot reuse any component. Not applicable for very small tips (micro-tabs).

with this type of tool design. Natoli has recently introduced the vented cap, which allows the entire assembled punch to be cleaned and dried without disassembly. The vent slots will enable the cleaning solution to pass around the bases of the tips and allow the use of compressed air to dry this critical area.

Micro Tab Punch

Small-diameter tips are quite delicate and can be easily damaged. The assembled tool lets users keep spares in stock and replace them as needed, minimizing downtime. The biggest challenge with assembled-type tools is assembly and cleaning. The alignment of the tips is critical, and any slight misalignment can cause damage to the tips. Any slight debris or material that interferes with the tool assembly can result in misalignment. As there are many mating parts and small crevices, cleaning is diﬃcult. It is recommended the tools be disassembled before cleaning, which adds time to the process. However, recent advances have been made

52 PHARMA machines & technology

Vented Caps

Another advantage to the assembled type is that materials and coatings can be customized for the various components to optimize tool life and performance.

Solid Type The solid type of punch is often considered more “user friendly” than the assembled one. As the name indicates, the solid-type punch is machined directly from one solid steel bar and can be cleaned like a typical single-tip punch. Many users prefer the solid type of punch as the handling, set-up, maintenance, and cleaning are identical to that of traditional single-

October - November 2023

visit us at

28th Nov. - 30th Nov. 2023

Hall-11. Stand-C39.

Tablet Tooling

A R T I C L E tip tooling. The disadvantage is any wear or damage to any of the tips will necessitate the entire punch being replaced, not just the tips. Implementing Multi Tip Tools The pros and cons listed above are some aspects to consider when implementing multi-tip tooling. Which punch type is best will depend on which characteristics are most desirable for a speci c product and process. For example, if tip wear is an issue, the assembled type may have the advantage. Still, if implementing multi-tip tools into an already validated process (including cleaning validation), the solid type may be the better option. Multi-tip tooling may also aﬀect some press operation and process parameters. Important considerations are: • Due to the complexity of tooling and the need for precise alignment, multi-tip tooling is recommended for turrets in new or like-new condition. It should be set up by experienced technicians. • As a greater volume of powder is being compressed, and more tablets are ejected per revolution, compression and ejection forces will likely be greater, which can lead to accelerated wear. This also results in greater friction and heat generation, which may be detrimental when compressing temperature-sensitive API's and can result in sticking for these products. •

A signi cantly larger powder volume is lled into each die due to the multiple bores, so the formulation should have good ow characteristics to ensure adequate and equal lling of all bores. The feeder settings, paddle, and base plate designs may also need to be modi ed. Turret speed/RPM may need to be reduced to increase feeder dwell time. The variation in the position of the die bores relative to the center of the die table may introduce variation in ll volume.

• Ensure downstream equipment such as de-dusters and coaters can handle the greater throughput of tablets. This may be especially critical for continuous manufacturing applications. • Tip layout and orientation are critical to take-oﬀ performance. Key angle and tip layout orientation can be customized by your tool vendor for speci c tablet shapes and make/model presses to optimize performance. Static build-up may further hinder the take-oﬀ of micro-tabs, and to resolve, the press may need to be tted with a deionized air system. • As the formulation moves through the feed frames faster, there is less resident time, and may reduce over-blending. • A greater number of tips allows for higher compression forces and may reduce the chance of overloading the tips. • For small diameter tablets (4mm or less), it may require the use of more sensitive force measurement for weight/thickness control and to prevent over-compression damage to the punch tips. As alluded to above, it is advised to evaluate and, if necessary, optimize a formulation, product, and process using single-tip tooling before implementing Fixed Indexable Head

Rotating Head

• It is more challenging to validate the tablet reject system, as single tablet rejection is impossible. All tablets produced by a single station of tooling are rejected.

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Tablet Tooling

A R T I C L E multi-tip tooling. This will provide the opportunity to recognize potential issues and rectify them at the R&D stage before investing in production scale tooling. Just like a formulation can be optimized to improve ow characteristics and compressibility, tooling vendors can also optimize tooling to overcome certain issues. For example, if high ejection and/or pull-down forces are causing accelerated head wear, limiting punch life, the tooling can be modi ed with rotating or xed-indexable heads. The rotating head allows a head to rotate independently of the punch body, evenly distributing wear while alleviating torsional stress on the tips (critical for micro tab tooling). The xed indexable head allows the user to remove a single pin, rotate the head 90°, and reinstall it so that a “new” portion of the head is exposed to the cam and pressure rolls. Undercut Dies/Shortened Lower Tips Micro tab production is often accomplished with

Note that undercut dies and shortened lower punch tips must be combined with shallow ll cams and effective lower punch retainers or nondrop cam/shim (to restrict the drop of the lower punch). It is the ll cam depth that determines how much the die can be undercut and how short the lower tip can become. Optimizing Multi-Tip Tooling Once a product has been selected for production using multi-tip tools, the rst decision made will be if the assembled type or solid type is preferred for that speci c product. As each tool type has various strengths, this may differ between different products. The next step will be on the number of tips and tip layout. This stage is important to discuss with your tool vendor. Tool size (B, D, or other), tablet size, and desired output will all factor into the number of tips on the punch. Take-off angle/orientation is another important factor to consider, and a reputable tool vendor can advise on potential take-off issues and offer an optimized tip layout plus key angle. Depending on the formulation properties, specialized steels or coatings may be needed to mitigate common issues such as sticking or premature wear. This is where data and observations from the R&D and scale-up stage using single-tip tooling will be quite valuable. Customized maintenance and set-up tools/kits are available to simplify the upkeep and setup of these more specialized tools.

Undercut Dies

multi-tip tooling and presents some unique challenges not encountered with more “normal” size tooling. Small-diameter tooling is most likely to fail due to bending/buckling of the lower tip, as the resistance to this bending/buckling is proportional to the length of the lower tip. Undercut dies, originally engineered by Natoli, are strongly recommended for all micro-tab designs (4mm smaller) for single-tip and multi-tip con gured tooling. Undercutting the die allows for the lower tip to be made shorter, thus increasing the strength and resistance to buckling.

58 PHARMA machines & technology

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Maintenance Kit

Meet us at 28th Nov. - 30th Nov. 2023

Hall-10. Stand-C02B.

Tablet Tooling

A R T I C L E Conclusion Multi-tip tools are the ideal way to increase production while minimizing cost notably. Although the cost of tooling is higher for these specialized precision tools, that cost is insigni cant compared to the alternative of buying a new press, building new compression suites, and hiring new operators, all to accomplish the same goal of increasing productivity. Multi-tip tools are ideal for many products and can be customized and engineered to alleviate many common tablet production challenges. Recognizing, addressing, and optimizing potential formulation and process de ciencies during the R&D and scale-up stages will allow eﬃcient implementation of multi-tip tooling at the production stage.

About the Author

Kevin Queensen Technical Service: Tooling and Tablets Mechanical Engineer (B.S.M.E.) Natoli Engineering Company

Kevin Queensen has been with Natoli Engineering since 2011 and is a degreed Mechanical Engineer. Kevin is an integral engineering team member, providing his educational expertise in problem-solving design concerns. He has also provided his product design knowledge in technical services and tablet production troubleshooting. Currently, he provides complete consultation with customers on tooling designs that will meet their needs and production requirements, while maintaining manufacturing standards and feasibility. He is one of Natoli’s in-house training instructors, educating sales teams and customers about tooling design and performance. Kevin has authored several industry-recognized technical articles on tooling design and performance for major pharmaceutical publications.

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Scan to Open DIGITAL MULTI TIP TOOLING GUIDE

Hygenic Design

A R T I C L E

Hygienic design Part 3

PUMPS, SEALS AND VALVES By Dr. TIM SANDLE

The hygienic design of equipment and utilities is of great importance in pharmaceuticals and healthcare to avoid contamination risks (both microbial and chemical). Good design, the aims and expectations of cleaning validation can be achieved. In the previous two issue, we discussed Surface Composition (Part 1) and vessels and Pipes (Part 2), this article is about Pumps, Seals, and Valves, The third article highlights the hygienic design considerations of pumps, seals, and valves. It also consolidates the key takeaways from the previous articles to discuss the important aspects of quality by-design and its regulatory implications The proper design of equipment and utilities plays a vital role in the pharmaceutical and healthcare industries in order to prevent contamination risks, both microbial and chemical. By implementing eﬀective design principles, the objectives and expectations of cleaning validation can be met. Failing to achieve good hygienic design not only poses a risk to the product but also has economic consequences, such as increased operating costs due to factors like higher energy consumption and additional plant downtimes (1).

accumulate. If pumps cannot be cleaned-in-place, the ease of disassembly for manual cleaning and the nature of material surfaces become crucial factors. Hygienic requirements should be addressed during the design and development stages, starting with the selection of suitable pump manufacturers who can demonstrate design compliance with industry standards. The hygienic design of equipment needs to be subsequently assessed by the user to show that the desired cleanability of the equipment can be achieved.

In the case of pumps, their cleanliness largely depends on their design, as an optimal hygienic design aims to minimize crevices and eliminate stagnant areas where bacteria and chemicals can

Similarly, valves need to be designed with hygiene in mind. It is imperative that valves work eﬃciently to control uids and that their housing sealing is consistently reproducibly cleanable. It should be “gap

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Hygenic Design

A R T I C L E free”. It is important that product residues do not accumulate in the gaps due to the low ow velocity in this area and hence eﬃcient cleaning becomes challenging. As for seals, their design should prevent soil and microbial build-up by being completely free of gaps under all operating conditions. Even the smallest gaps and crevices can harbor microorganisms or chemical residues, potentially leading to product contamination (2). This article examines the essential hygienic design features of pumps, valves, and seals, and synthesizes the content covered in the three-part article series.

Pumps It's crucial that pumps have self-draining capabilities. When self-drain is not possible, due to design or operational constraints, Pumps can be moved into a position to be drained. Pumps should also have open crevice-free hygienic joints for optimal cleaning. Mono pumps should be avoided because of their poor design and potential for product impeller breakup. Tri-lobe pumps, in contrast, are a well-liked hygienic design. The lobes should be positioned carefully to prevent abrasion. It is important to be aware of the connections and to avoid products becoming trapped. Additionally suggested are peristaltic pumps. This kind of pump operates by gently pumping a tube. The peristaltic pump has advantages when used with shear-sensitive products and specialized equipment, such as a tube, is needed (3). To calculate the ow rate through a pump (single acting plunger or piston pumps), the following calculation can be used: Q = DP2 × L × n × N × π / 924 Where: Q = Flow Rate in gallons per minute DP = Plunger/Piston Diameter in inches L = Stroke Length in inches n = Number of Plungers/Pistons N = Speed of pump in revolutions per minute π = Pi = 3.14159 Hence: Flow Rate [GPM] = (Plunger Diameter [in])2 × Stoke

64 PHARMA machines & technology

Length [in] × Number of Plungers × Pump Speed [RPM] × 3.14159 / 924 As an example: • Plunger Diameter = 3.5 inches • Stroke Length = 6 inches • Number of Plungers = Triplex = 3 • Pump Speed = 100 RPM And: (3.5 [in])2 × 6 [in] × 3 × 100 [RPM] × 3.14159 / 924 = 74.97 GPM

Seals The design of sealings is one of the major aspects of hygienic design. Improperly selected seals represent areas where contaminants can reside. The sealing design needs to avoid the accumulation of soil and microbes and therefore has to be 'gap free' under all operation conditions. Even very small gaps and crevices can harbor a large population of microorganisms and hence this can be a source of product contamination. Areas around shaft seals should not contain deep annular crevices and the seals must be cleanable. A hygienic seal design can protect process uid from environmental contamination. The use of springs in the product contact area should be avoided.

Valves Eﬀective ow control and sampling systems require essential valves in closed systems, complex processes, and complex technologies commonly found in the pharmaceutical industry. The valves play a crucial role in regulating, directing, and controlling uid ow by opening, closing, or partially obstructing it within a system. This functionality operates in conjunction with pressure diﬀerentials, as uids naturally ow from higher to lower pressure areas. Various types of valves can be utilized for processing purposes, ranging from unhygienic options like ball valves to hygienically designed butter y valves. A ball valve is a quarter-turn valve that employs a hollow, perforated ball to manage ow. It opens when the ball's hole aligns with the ow and closes when pivoted 90 degrees by the valve handle. On the other hand, a butter y valve serves to isolate or regulate uid ow. Its closing mechanism consists of a rotating

October - November 2023

Hygenic Design

A R T I C L E disk, commonly referred to as the "butter y," mounted on a rod. When fully closed, the disc completely blocks the passageway, while a quarter turn in the fully open position allows unrestricted uid passage.

body with two or more ports, an elastomeric diaphragm, and a "weir or saddle" or seat upon which the diaphragm closes the valve. The valve body may be constructed from plastic, metal, wood, or other materials depending on the intended use. There is a possibility of a tear in the diaphragm valve. These tears can cause contamination from uids that get entrapped in the diaphragm. Diaphragm tears can be hard to detect since the pressure boundary of the diaphragm is not breached, the in-line instrumentation does not detect a system problem. There are some hygienic diagram valves available; these have valve bodies that are made of stainless steel and wetted surfaces. Such valves are electropolished or machined to a ne nish, as designed to be cleaned-in-place.

Image 2: Ball valves (Heather Smith / Alloy Valve Stockist, licensed under a Creative Commons Attribution 3.0 License).

A further good design feature with valves is the use of zero deadleg valves which are used to minimize deadlegs in critical areas of the piping system. In less critical areas, it was permissible for valves to be connected with tees or bends.

Image 3: Butter y valve (Alloy Valve Stockist, licensed under a Creative Commons Attribution 3.0 License).

Valves that are considered unhygienic are those with housing sealings that cannot be reproducibly cleaned, allowing residue buildup in the gaps, due to low ow velocity thus eﬃcient cleaning becomes impossible. Residues not only present a risk for contamination of subsequent product batches but they are also a safe harbor for microorganisms to grow and protect them during sterilization or disinfection. These residues increase the risk of microbial contamination of subsequent product batches produced on the same process line. In contrast, hygienic valves act as both the static seal (shell seal) and a dynamic seal (weir shutoﬀ ). (4) Diaphragm valves (or membrane valves) The valve

66 PHARMA machines & technology

Image 4: Zero dead leg valve (Aspeco, licensed under a Creative Commons Attribution 3.0 License).

Mixers Mixing in pharmaceutical manufacturing serves various purposes, such as combining raw ingredients, preparing emulsions, reducing particle size, conducting chemical reactions, manipulating rheology, dissolving components, and facilitating heat transfer. Consequently, many pharmaceutical product lines utilize diﬀerent types of mixers to process raw ingredients, handle intermediates, and prepare the

October - November 2023

Hygenic Design

A R T I C L E nal product. The size of the mixer depends on the required throughput. It is crucial for mixers to be easily cleaned to prevent the contamination of chemicals between batches (5). To prevent batch-to-batch contamination, CIP and Steam-in-Place (SIP) capabilities are typically incorporated, along with features like air-purged seals and custom-designed discharge valves.

pitched to ensure self-draining, and surfaces should be as smooth and ush as possible. Other considerations for hygienic design In addition to the main areas of hygienic design mentioned earlier, it is also important to consider the following: • Hygienic design of heat exchangers, this includes double-plated exchange plates to prevent leakage, ensuring they are fully drainable, and incorporating a failsafe mechanism for the coolant/heating side. • Have a close look at the gasket, seal areas, and product traps, to ensure they are eﬀective in maintaining hygiene. • Ensuing that lter housings are drainable.

Image 5: Powder mixer in a pharmaceutical facility (Adinhath, licensed under a Creative Commons Attribution 3.0 License).

Instruments The instrumentation used to assess the process also needs to be hygienic. Key criteria include: • The materials used should be resistant to corrosion and easy to clean. One option is to use 316L stainless steel with a ne surface nish. (aiming for a Ra surface reading of 0.51 µm or better). It should be noted that the processes involved in making some active pharmaceutical (API) ingredients are highly corrosive and may demand more exotic alloys, such as those with higher nickel levels.

• Any crevices and corners where bacteria and other contaminants can accumulate should be eliminated. Welds need to be smoothed both inside and out, and interior corners should have a radius. Conventional pipe threads should never be used. • Pockets and dead legs in piping should be avoided. Liquids should not have any areas where they can be trapped or retain residues. Piping should be

68 PHARMA machines & technology

Engineers, quality personnel, microbiologists, and others must grasp the fundamentals of hygienic design in order to provide eﬀective oversight. The microbiologists must be included early in plant, and equipment acquisitions and updates (such as the change control process). This is crucial in case of any modi cations during installation. Such actions necessitate risk assessment, which focuses on topics such as: How will risks be controlled? How will the system be sanitized after the task is completed? How many samples are needed to evaluate the impact of the work? To attain these objectives, microbiologists must collaborate successfully with engineering, maintenance, and production units to keep sanitary practices high and at the forefront of operations.

Maintaining hygienic security and good quality design considerations Once systems are correctly constructed and operational, it is critical to maintain hygienic oversight, inspect systems on a regular basis, and review the available data, whether physical, chemical, or in relation to bioburden. Eﬀective planned preventative maintenance should be in place, and any type of replacement should be made at suitable time intervals. Preventative maintenance, which entails a program and strategy for maintaining equipment, can help facilities save money and reduce downtime. Adopting a failure-oriented mentality is not a smart

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Hygenic Design

A R T I C L E practice because the failure outcome can provide considerable microbiological danger. Good hygiene design principles are outlined with examples discussed in this article. Effective hygienic systems and equipment in units is a regulatory expectation, such as the U.S. Code of Federal Regulations, notably Subpart C - Building and Facilities Section 211.42 Design and Construction Features, which states: • Adequate size, construction, and position must allow for easy cleaning, maintenance, and proper operation. • Plan adequate space for the orderly positioning of equipment and materials to avoid mix-ups and contamination. • Design the adequate ow of materials and persons to prevent contamination. A sound approach to hygienic design is also in keeping with ICH Q8, which de nes the design space on the basis that quality cannot be tested into the product but has to be built in through good design (6). ICH Q8 needs to be considered alongside the principles of quality risk management, as presented in the sister guideline document ICH Q9 (7). Quality risk management is most effective when used (8): • Prospectively. • On the basis of straightforward, objective models created with the greatest science and engineering information, knowledge, and tools available. • Led by an objective, interdisciplinary, and experienced team of subject matter specialists. Together, these two standards represent 'quality by design'. Quality by Design is de ned as "a systematic approach to development that begins with prede ned objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management" in the ICH Q8 guideline. This philosophy includes: • Product quality and performance can be assured by designing efficient manufacturing processes. • Product and process speci cations are based on a scienti c understanding of how process factors affect product performance. • Risk-based regulatory techniques for scienti c

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comprehension and process control connected to product quality and performance. • Related regulatory regulations and actions are revised to re ect current scienti c understanding. • Quality assurance as a continuous process. While a comprehensive contamination control strategy, attention also needs to be given to the control of the environment (as with cleanrooms), control of personnel and traﬃc movement, and process design. These concerns can be presented as three aspects (9): • Process: unit operations, grouping of unit operations into logical operational units; appropriate process equipment, components, and instruments; automated process control systems; and input and in-process materials and products. • Facilities: structures, environmental systems, layouts, operational ows, logistical support, utility systems, and other building control systems such as the building management system. • Infrastructure: Practises, procedures, people (training, discipline, and quali cation), maintenance systems, and automated procedural control systems that regulate the facility and process elements (such as manufacturing execution systems, electronic batch records, and so on). This chapter primarily focuses on process design, which is a crucial aspect among others. It's important to note that other aspects, especially in understanding how equipment meets hygienic design requirements. It plays a signi cant role in understanding how poor practices can inadvertently re-contaminate. The pharmaceutical sector has drawn inspiration from the food industry to improve hygienic design practices. However, the pharma industry has historically lagged behind the food industry in terms of innovations related to equipment speci cations, design, and cleaning (10). Cleaning is a complex process in uenced by various factors, including the type of dirt to be removed, cleaning duration, temperature of the cleaning agent, and the hydrodynamic force of the moving liquid (10). This article, along with the other two in this series, discusses essential aspects of equipment hygiene and

October - November 2023

Hygenic Design

A R T I C L E cleanliness, providing measurements and calculations to assess the hygienic status eﬀectively. Summary As mentioned in this series of articles, improperly speci ed and designed processing equipment can have a negative impact on the microbiological and chemical safety of the product, and may even lead to physical contamination. Therefore, it is crucial that all equipment that comes into contact with the product is designed with hygiene in mind. The application of hygienic design involves reviewing all relevant project stages. This can be facilitated by project management tools that aim to minimize risks and identify the most cost-eﬀective designs to maintain the desired hygiene levels. This article was the third and nal in a series focusing on hygienic design concepts. Drawing on some of the points raised in the previous articles, a quality-driven approach to hygienic design should consider: Material

Surfaces

Construction

Corrosion resistant

No holes

Dead leg free

Chemically resistant

No gaps

Corners > 90°

Nontoxic

No crevices

Radii > 3 mm (ideally, > 6 mm)

Non contaminating

No folds

No sharp edges

Nonabrasive

Cleanable

No metal to metal connections (bolds/nuts)

Non absorbing

Capable of being disinfected

Self-draining

No in uence on product Capable of being sterilized, if required Temperature resistant

Roughness Ra ≤ 0.8 µm

Low number of gaskets Stable gap-free sealing construction

The hygienic design of pharmaceutical processing is crucial for ensuring the microbiological safety and quality of products. It helps prevent high microbial counts, toxins, and chemical residues in products at various stages of manufacturing. By prioritizing hygienic requirements and using proper equipment that is operated and maintained correctly, a facility can produce safe and high-quality products.

ABOUT THE AUTHOR Tim Sandle is the author of the book Digital Transformation and Regulatory Considerations for Biopharmaceutical and Healthcare Manufacturers, Volume 1: Digital Technologies for Automation and Process Improvement, available via the PDA Bookstore: https://www.pda.org/bookstore/productdetail/5897-digital-transformation-volume-1

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A new book by Tim Sandle available from the PDA titled 'Industrial Pharmaceutical Microbiology’ to view e-book scan the QR code

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News & Updates

REVIEW

Spectacular Success of the "Revision of Schedule-M" Workshop organised by CDSCO and IDMA in Mumbai

The Central Drugs Standard Control Organisation (CDSCO) in association with the Indian Drug Manufacturers' Association (IDMA) organised a workshop on "Revision of Schedule-M" on 30 Sep 2023 in Mumbai. Dr. S Eswara Reddy, Joint Drugs Controller of India, was the Chief Guest and keynote speaker. The event was a spectacular success with in-person attendance of more than 300 participants and 6,000+ viewers online. The objective of the workshop was to make the participants aware of the proposed changes to the Schedule-M and prepare for implementation at the earliest. To create awareness amongst drug manufacturers about good manufacturing practices (GMP) requirements to ensure quality of medicines, workshops on Revision of Schedule-M were organised across India in Sep 2023 by CDSCO in partnership with IDMA. Schedule-M prescribes requirements to the manufacturing plants of pharmaceutical companies for maintenance, manufacturing, control and safety testing, storage and transport material, written procedures and records, and traceability etc. The revised GMP guidelines have come at a relevant time when India is reinforcing itself as the global pharmaceutical manufacturing hub. Dr. Reddy was earnest and generous in elucidating the fine print of Revised Schedule-M. The audience was touched by his articulation - it had relevant examples and anecdotes. He also noted his cognizance and understanding of industry's challenges and offered guidance on how to navigate successfully in an evolving regulatory environment. He further described need for revision of Schedule-M, GMP requirements keeping in mind current changes in the concept of quality of drugs, convergence of Indian standards with global standards, and technological advancements in manufacturing and testing of drugs. The Government of India (GoI) has notified draft

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April - May 2023

Schedule-M in October 2018 and had serious of meeting with all drug manufacturers associations and other stakeholders. It is now under active consideration of the Ministry of Health and Family Welfare, Government of India. Larger companies with a turnover of over 250 Crores INR have been asked to implement the changes within 6-months, while medium and small-scale enterprises with turnover of less than 250 Crores INR have been asked to do so within 1-year. The new version of Schedule-M is designed to ensure compliance to standards of drugs, promote exports, promote innovation and also to build trust and confidence on quality of drugs manufactured and sold. Page 2 of 2 Dr. Viranchi Shah, IDMA's National President, in his message extended gratitude to CDSCO and Dr. S Eswara Reddy. He added, "The Indian pharmaceutical industry welcomes Revised Schedule-M. IDMA member companies are committed for ensuring adoption and ongoing compliance with determination and discipline. Today's event was in continuation of momentum by IDMA in seeking greater collaboration and alignment between government, companies, regulators, and other stakeholders." Shri Mehul Shah, Honourable General Secretary of IDMA, had the honour of delivering the opening remarks and vote of thanks. He reiterated the industry's positive response to Revised Schedule-M by stating that Indian pharmaceutical industry is committed in its endeavour to ensure manufacturing and supply of high-quality, safe, efficacious, innovative, and affordable medicines to patients and consumers in India and worldwide. Shri Daara Patel, Secretary General of IDMA, and his team were lauded for excellent planning and execution of the event by dignitaries and participants. Daara added "Under Dr. Viranchi Shah's visionary leadership, IDMA has organised a series of events in the last 2- years to advance cause of the nation and the Indian pharmaceutical industry especially MSME sector. We will continue to organize more such value-additive events in future."

News & Updates

REVIEW CREATING FUTURE READY ORGANISATIONS5th Annual Pharma Manufacturing & Automation Convention 2024 Having all the discussion on digitization and MES need to

Distinction Business Media's fifth Yearly program on computerization and assembling occurred in Novotel Hyderabad Conference hall on October fifth sixth. The program saw a few introductions, contextual investigation based meeting, bunch conversations and gathering exercises by industry pioneers and arrangement suppliers. The subject of the gathering was tied in with setting the base for little and fair size organizations for digitization approach and upskilling the top pharma organizations to be at their A game. The meeting started with a warm greeting from Ms. Guneet Kaur Hayer, Overseeing Overseer of Greatness Gathering, making way for an uncommon two-day instructive excursion zeroed in on quality. The debut light lighting had Ms. Guneet, Mr. K Kulbhushan-Dr. Reddy's, Dr. Damodharan M-Sai Life Sciences Ltd, Dr. Anitha Kumari-Novartis, Mr. Seshasai Kandrakota-Type Advancements, Prabir Kumar Buddy Alkem labs and Suryansh Rana-Greatness Business Media. Mr. K Kulbhushan from Dr. Reddy's launched the day with the primary meeting on making Future Prepared Associations. Subsequent to setting the setting, the occasion saw an intricate figuring out on computer based intelligence and ML Rules by FDA and other administrative bodies for pharma producing organizations by Mr. Prabir Kumar Buddy from Alkem Labs; trailed by Advanced Guide Techniques for shopfloor by Rakesh Kandi from occasion's Platinum Accomplice; Type Innovations.

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zero in on information security as the critical component to stay away from obstacles; a short chat on Information Security and Uprightness as forerunners to robotization was driven by Mr. Prabhakar Rao from Natco Pharma, Exposing the Fantasies around Digitization by Ciaran O'Keeffe and afterward a point by point board conversation that was likewise communicated real time on Prominence's YouTube channel "Pharma and Then some" with an inside and out understanding on Beacon Ventures by K Kulbhushan, Sunil Kumar-CTO from Joyous and B Krishna Mohan- CIO from Granules. After a portion of a day of introductions and conversations; the occasion saw contextual investigation by Dr. Satya Moturi on long term excursion of Organic E and about Paonta Sahib plant of Natural E. The day 1 finished with a short chat on IT/OT Coordination by Anup Garg and an exceptionally special gathering action meeting by Sushil Barkur from Alkem Labs on the need of labor supply and asset the executives, computerized education, deskilling, upskilling and multiskilling of the staff in pharma fabricating plants. The day 2 of the Eminence Business Media conference focused on automating processes and integrating all processes to work as one. It featured sessions on BMR, Unified Manufacturing Systems, One Plant One System Approach, SaaS Journey of Life Sciences Industry, presentation based sessions, Q&A round, and Lego Serious Play activity. Partners from Caliber Technologies, MasterControl, ABB India, Körber Pharma, Hitachi Hi tech, Ecubix, CN Water, Aizen Algo, Lonza, Rephine and QTech Info Solutions partnered at the conference.

visit us at

28th Nov. - 30th Nov. 2023

Hall-9. Stand-C12.

PM&T_OCT-NOV-23

PM&T_AUG-SEPT-23