INTRODUCTION: INDIA’S STERILE MANUFACTURING UNDER THE REGULATORY SPOTLIGHT
Genesis and growth of the Indian pharma industry
The Indian pharmaceutical industry traces its origins to the early 20th century, when local entrepreneurs began to challenge the dominance of foreign firms in the British colonial era. Following independence in 1947, the Indian government prioritised healthcare self-sufficiency by cultivating a strong domestic drug manufacturing base. A watershed moment came with the Patents Act of 1970, which allowed process patents instead of product patents. This enabled Indian companies to reverse-engineer patented drugs and produce them at scale, significantly improving affordability and access to essential medicines. As a result, the industry witnessed exponential growth in the 1980s and 1990s, particularly in the generics segment.
Foray into highly regulated markets:
With economic liberalisation in the 1990s and growing technical competence, Indian firms began targeting regulated markets such as the United States, Europe, and Japan. This transition was marked by strategic investments in regulatory-compliant manufacturing facilities, advanced quality systems, and R&D infrastructure. By 2024, more than 750 Indian facilities were registered with the U.S. FDA, and over 200 had received approvals for sterile injectable drugs and complex formulations (1). This scale of global engagement reflects India’s capability to meet the stringent quality expectations of major health authorities including the U.S. FDA, EMA, MHRA, and TGA.
Commitment to quality and global recognition:
India’s emergence as the “Pharmacy of the World” is underpinned by its unwavering commitment to quality, cost-effectiveness, and supply reliability. Indian pharmaceutical companies supply more than 60 per cent of global demand for vaccines and over 40 per cent of generic medicines consumed in the United States (2). Several firms have developed internal compliance frameworks aligned with ICH Q10 and WHO GMP standards, positioning themselves as preferred partners in global supply chains.
Economic contribution and export performance:
The pharmaceutical sector plays a pivotal role in India’s economic landscape. In FY 2024–25, India’s pharmaceutical exports exceeded USD 30.3 billion, up from USD 27.9 billion the previous year, a year-on-year growth of approximately 9 per cent (3). The U.S. continues to be the largest importer, accounting for over 33 per cent of total Indian pharma exports. The sector contributes about 1.7 per cent to India’s GDP and employs over 3 million people directly and indirectly.
Sterile drug products: Volume and value:
Sterile formulations, including injectables, ophthalmics, infusions, and biologics represent a strategically important segment of India’s pharmaceutical exports. While they comprise less than 10 per cent of the total export volume, they contribute approximately 20–25 per cent of the total export value due to their higher unit cost and complexity. According to the Pharmaceuticals Export Promotion Council of India (Pharmexcil), injectables are among the top five exported formulations by value from India, with strong demand in regulated markets such as the U.S., EU, and Latin America.
This growth is further driven by global shortages of sterile products, an expanding biologics pipeline, and the demand for emergency-use therapies including vaccines. For instance, India’s role as a major supplier of COVID-19 vaccines underscored its capabilities in high-volume sterile manufacturing (4).
Leading Indian sterile drug manufacturers:
Several Indian pharmaceutical companies have established themselves as key players in the sterile drug manufacturing space, exporting to the U.S. and EU markets. Notable among them are:
- Sun Pharmaceutical Industries
- Dr Reddy’s Laboratories
- Cipla
- Lupin
- Zydus Lifesciences
- Aurobindo Pharma
- Gland Pharma
These companies have invested heavily in advanced manufacturing technologies, compliance systems, and workforce training to meet the stringent requirements of global regulators. These firms operate multiple sterile sites approved by the FDA, EMA, and other regulators. Their investment in isolator technology, automated visual inspection, lyophilisation, and container closure integrity testing demonstrates a proactive approach to compliance and operational excellence.
Trends in regulatory inspections:
Over the past several years, Indian pharmaceutical facilities, particularly those engaged in sterile manufacturing have experienced intensified regulatory scrutiny. According to the U.S. FDA’s Foreign Inspections Dashboard, India consistently ranks as the most frequently inspected country outside the United States. In FY 2023, India accounted for approximately 27 per cent of all FDA foreign drug inspections, with a notable proportion focused on sterile manufacturing sites.
Several factors have contributed to this trend:
- Increased complexity of sterile operations and the higher risks associated with parenteral products.
- Recurring issues related to aseptic techniques, environmental monitoring, and data integrity.
- A global dependency on Indian injectables, especially in the generics and critical care segments.
Furthermore, FDA Warning Letters issued between 2020 and 2024 show a disproportionately higher number of citations for sterile product manufacturers. Common deficiencies include inadequate smoke studies, non-compliant aseptic practices, insufficient microbial controls, and gaps in media fill execution (5). These inspection outcomes underscore a rising expectation for robust contamination control, well-established quality systems, and scientific rationale in facility design and operations.
Shift towards unannounced inspections:
In a press release dated May 6, 2025, the U.S. FDA reaffirmed its strategic intent to increase unannounced inspections at overseas facilities, particularly those manufacturing essential or shortage-listed medicines for the U.S. market. This approach aims to eliminate preparedness bias and ensure that real-time compliance is maintained. Indian facilities, as significant contributors to the U.S. sterile drug supply chain, are likely to be under heightened surveillance in this context (6).
Stringent compliance for sterile products:
The sterile manufacturing environment poses unique challenges due to the risk of microbial and particulate contamination. Since these products bypass the body’s natural barriers, any breach in aseptic assurance could result in patient harm, including sepsis or death. Regulatory agencies, therefore, mandate the strictest GMP standards for sterile facilities, including ISO 5/ Grade A cleanrooms, validated aseptic practices, real-time environmental monitoring, and robust contamination control strategies as outlined in EU GMP Annex 1 and FDA’s Sterile Drug Products Guidance.
Why this article? a practitioner’s perspective:
Against this dynamic and high-stakes backdrop, Indian sterile manufacturers must now navigate a complex regulatory terrain. The increasing rigor of FDA inspections, coupled with the evolving expectations around contamination control, quality culture, and scientific risk assessment calls for deep introspection and systemic transformation.
This article presents our consolidated perspective on the recurring challenges and deficiencies commonly encountered by Indian sterile drug manufacturing facilities, as observed through our engagements over the past eight years. During this period, RedLotus Pharmtech. has supported numerous companies in investigating, responding to, and remediating US FDA Form 483 observations, warning letters, import alerts, and other compliance concerns. Our insights draw from actual case work involving plant-level assessments, risk-based investigations, process revalidations, and regulatory strategy development providing a practitioner’s lens into what truly matters during an FDA inspection and how Indian firms can course-correct to achieve compliance excellence.
India’s sterile pharmaceutical manufacturing sector has made significant strides in aligning its infrastructure and operations with global regulatory expectations. Many facilities catering to regulated markets are equipped with state-of-the-art plant layouts, Grade A/B cleanrooms, and manufacturing technologies that rival the best globally. From advanced isolation and containment systems to fully automated Clean-In-Place (CIP) and Steam-In-Place (SIP) capabilities, and from electronic batch records to data systems compliant with 21 CFR Part 11, the sector has demonstrated its ability to adopt and implement modern technological solutions.
Yet, despite these technological investments, recurring compliance gaps continue to emerge, primarily in the areas of system design, decision-making, and data integrity. Based on our on-ground experience, the following patterns are frequently observed:
- Design basis weaknesses:
Facilities often lack well-documented scientific rationales or fail to present a robust justification for design choices, procedural controls, and process parameters. This is particularly evident in cleanroom classification, HVAC zoning, process hold times, media fill program, aseptic practices, and filtration validation. The root of this issue often lies in incomplete/ inaccurate application of Quality Risk Management (QRM) principles and/ or a lack of complementary data/ sound scientific reasoning to support it.
- Gaps in critical thinking and deviation handling:
In many cases, critical thinking during investigation and problem-solving is inadequate. Investigations into deviations, OOS results, or media fill failures are often superficial or biased toward pre-conceived conclusions. There is a tendency to resolve the symptom rather than understand and address the root cause, weakening the effectiveness of corrective and preventive actions (CAPAs).
- Data Integrity (DI) vulnerabilities:
The deficiencies in rationale and decision-making often manifest as breaches in data integrity, either due to unintentional lapses, lack of awareness, or, in some cases, deliberate manipulation. Poor documentation practices, backdating, missing metadata, and improper audit trail reviews are frequently cited in FDA Form 483s and warning letters, particularly in relation to environmental monitoring, laboratory controls, and electronic records.
Through our consulting engagements over the past eight years, RedLotus Pharmtech. has partnered with more than 20 sterile drug product manufacturers, ranging from large global players to mid-sized Indian exporters, to address a wide spectrum of regulatory and compliance challenges. The insights presented in this article are grounded in the practical learnings gained from these assignments, which have included:
- Comprehensive plant-wide gap assessments against FDA and EU GMP expectations
- Execution and oversight of risk-based investigations for contamination events, media fill failures, and repeated deviations
- Support in process and cleaning revalidations, including hold-time studies, filter integrity, and aseptic process validation
- Preparation and defence of regulatory responses to Form 483s, Warning Letters, and Import Alerts
- Development and implementation of remediation plans covering facility upgrades, procedural improvements, and quality system redesign
- Design and delivery of quality culture transformation Programs, including leadership alignment and behavioural change initiatives
- Strengthening of data integrity controls, including audit trail reviews, ALCOA+ (Attributable, Legible, Contemporaneous, Original, Accurate – plus Completeness, Consistency, and Enduring Availability ) training, and system governance audits
This article distils those experiences into a focused analysis of what truly matters during an FDA inspection – not just in terms of procedural compliance, but in cultivating the mindset, rationale, and system robustness needed to sustain long-term regulatory confidence. It reflects a practitioner’s lens on the common pitfalls, overlooked areas, and transformative opportunities that can help Indian sterile manufacturers evolve from reactive remediation to proactive quality leadership.
US FDA EXPECTATIONS: A HIGHER BAR FOR STERILITY ASSURANCE
The manufacture of sterile drug products represents one of the most technically demanding and highly regulated segments of pharmaceutical production. Unlike oral solids, sterile injectables and ophthalmics bypass the body’s natural defences and are administered directly into sensitive tissues or the bloodstream. This makes sterility an absolute and non-negotiable quality attribute. Consequently, regulatory agencies, led by the U.S. Food and Drug Administration (FDA) enforce significantly higher expectations when it comes to design, controls, monitoring, and assurance systems for sterile manufacturing.
Sterility as a Critical Quality Attribute:
Among all the Critical Quality Attributes (CQAs) of a sterile drug product, sterility is uniquely distinct both in its definition and in the approach required to ensure it. While most CQAs – such as assay, impurity profile, fill volume, viscosity, pH, and visible/sub-visible particulate matter – can be directly measured through validated physico-chemical or instrumental methods that yield quantifiable results, **sterility stands alone as an absolute and qualitative attribute.
According to the United States Pharmacopeia (USP <71>), sterility is defined as the complete absence of viable contaminating microorganisms in a product. It is an absolute term, meaning that a drug product is either sterile or it is not – there is no gradation or partial state of sterility. This all-or-nothing nature of sterility introduces a unique regulatory and scientific challenge: it cannot be “measured” in the same way as other attributes; it can only be assured.
The limitation of sterility testing:
While the sterility test is a mandated part of the regulatory release process for sterile drug products, its utility as a direct indicator of product sterility is fundamentally limited. It involves incubating a limited number of sample units in microbial growth media under specified conditions and interpreting a lack of growth as evidence of sterility. However, due to the probabilistic nature of microbial contamination, this test cannot statistically guarantee the sterility of a batch, especially when the contamination level is very low or when non-uniform contamination occurs.
For example, sampling 20 units from a batch of 10,000 units cannot confirm sterility across the batch with a high degree of certainty, especially if contamination is non-homogeneous. In essence, a passing sterility test provides limited assurance, and a failing test is often catastrophic for batch disposition and regulatory implications, even though the root cause may remain elusive.
As the FDA and other regulators have repeatedly emphasised, sterility must be built into the product through the design and control of the manufacturing process, not verified through end-product testing. This concept underpins modern approaches to sterile product assurance, where greater importance is given to aseptic process controls, facility design, operator practices, and environmental monitoring as part of a holistic sterility assurance system (SAS).
Terminal sterilisation vs. aseptic processing and Sterility Assurance Level (SAL)
Sterility Assurance Level (SAL) is most precisely applicable in terminal sterilisation, where the product is sterilised in its final sealed container using physical methods such as moist heat, dry heat, or radiation. In such cases, an SAL of 10⁻⁶ means there is less than a one-in-a-million chance of a non-sterile unit surviving the process.
The concept of Sterility Assurance Level (SAL) provides a scientific framework for understanding the probability-based approach to ensuring sterility. For most parenteral products, the target SAL is 10⁻⁶, meaning there is a one in a million chance that a unit is non-sterile after going through a validated sterilisation or aseptic process. Achieving this SAL requires a tightly controlled process validated through media fills, biological indicator studies (for terminal sterilisation), and rigorous contamination control strategies.
In contrast, aseptic processing involves combining sterile components in a sterile environment without a terminal sterilisation step. Here, the concept of SAL is more theoretical—it cannot be precisely measured but must be demonstrated through a combination of rigorous environmental controls, validated aseptic simulations (media fills), and comprehensive contamination control strategies. This makes aseptic processing inherently more vulnerable and subject to stricter regulatory expectations than terminally sterilised products.
Thus, while attributes like fill volume or assay have a defined acceptance range and can be verified with precise measurements, sterility must be ensured through risk-based process design, validation, and operational control.
In short; while the other CQAs are measured and quantified, sterility is assured through a validated and controlled process.
This fundamental distinction underscores the elevated expectations the FDA places on sterile drug product manufacturers, particularly in their design justification, process control, and contamination risk mitigation strategies. The industry must understand that the sterility test is not a guarantee, but a minimal requirement – it is the process that ensures sterility, and that process must be scientifically designed, rigorously controlled, and thoroughly documented.
FDA’s focus areas in sterile manufacturing inspections:
Based on inspection trends and enforcement actions observed over the past five years, the FDA places heightened emphasis on the following areas during sterile facility inspections:
- Contamination Control Strategy (CCS): FDA expects firms to implement a comprehensive and integrated CCS, in line with EU GMP Annex 1 (2022). This includes risk-based identification of contamination vectors, proactive mitigation controls, and lifecycle review of effectiveness.
- Facility and Cleanroom Design: Facilities must demonstrate unidirectional personnel and material flow, pressure differentials, segregation of critical areas, and proper zoning aligned with ISO and Grade A/B/C/D classifications. Poorly justified or legacy designs are often questioned.
- Aseptic Practices and Operator Qualification: FDA scrutinises the execution of aseptic techniques, including glove disinfection, interventions during fills, and personnel behaviour. Operator qualification, gowning validation, and requalification Programs must be robust and routinely assessed.
- Environmental Monitoring (EM): Firms are expected to implement a risk-based EM Program that includes real-time particle monitoring in Grade A zones, microbial air and surface sampling, trend analysis, and alert/action level justifications. The placement of EM devices and the frequency of monitoring during routine and media fill operations are closely examined.
- Process Simulation (Media Fills): FDA views media fills as a critical validation of aseptic process capability. Any deviation or contamination event during a media fill must be thoroughly investigated, and batch release practices following failed simulations are carefully scrutinised.
- Critical Utilities and Equipment: The agency assesses the design, qualification, and monitoring of critical utilities such as WFI, compressed air, HVAC systems, and automated sterilisation cycles. Equipment cleaning validation and maintenance records are also subject to review.
- Data Integrity in Aseptic Processing: There is no tolerance for data manipulation or poor documentation practices in aseptic areas. FDA inspectors frequently review audit trails, time-stamped EM records, deviation logs, and manual entries for completeness, consistency, and compliance with ALCOA+ principles.
References:
1. Source: Pharmexcil, 2024 Annual Report
2. Source: IBEF, 2024
3. Source: Ministry of Commerce & Industry, DGCI&S, 2025
4. Sources: (a) Pharmexcil Annual Report 2023–24, (b) India Brand Equity Foundation (IBEF) – Indian Pharmaceutical Industry Report, April 2024, (c) DGCI&S Export Data, Ministry of Commerce & Industry, Government of India, and (d) CRISIL Ratings: “India’s Pharma Exports to Grow by 6–8% in FY25” March 2024
5.Sources: U.S. Food and Drug Administration, FDA Foreign Inspections Dashboard (https://datadashboard.fda.gov/oii/index.htm) U.S. FDA Warning Letters Database (https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters).
6. Source: FDA.gov, 2025 Policy Update on Foreign Surveillance Program (https://www.fda.gov/news-events/press-announcements/fda-announces-expanded-use-unannounced-inspections-foreign-manufacturing-facilities)