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Never too early for QbD


Excipients make up more than 90 per cent of each pill or tablet we consume but have not been a major focus of regulators in the past. With a significant number of drug recalls traced to inconsistent quality of excipients and faulty product design, the Quality by Design approach must be implemented as early as possible in the drug development lifecycle. Recent regulations and initiatives have attempted to modernise this segment of the pharma industry

Good manufacturing practices (GMPs) are the foundation of the pharmaceutical sector, as they assure the patient that her medicines actually contain what they should, and will not harm her health further. Adherence to GMPs guarantee quality medicines and regulators like the US Food and Drug Administration (FDA), and European Medicines Agency (EMA), have taken the lead to demand more stringent quality standards each year. India’s drug quality watch dog, the Central Drugs Standard Control Organization (CDSCO) has also increased the level of its scrutiny of late. (See a previous story:

These quality standards have evolved from testing the quality of the finished final product to testing the inputs as well as design of the entire production cycle, right from the formulation development stages. In other words, not quality by testing (QbT) of the final product but quality by design (QbD) of the process, including sourcing input ingredients of the desired quality.

Industry observers point out that a lot has changed in terms of reviewing abbreviated new drug applications (ANDAs). Regulators have on occasion resorted to the Refusal to Receive (RTR) option if the application does not contain evidence that the products were developed in compliance with the principles of QbD.

In some cases, if serious lapses in GMP compliance of the facility are found in the application, a complete response letter or its equivalent which is a warning letter (WL) may be issued. Thus a new approach in which an integrated quality team reviews dossiers, focussing on the possible GMP deficiencies of the concerned manufacturing plant, is very crucial. This will close the gaps between drug development and scale up.

Dr Sanjit Singh Lamba

Putting the regulatory evolution into perspective, Dr Sanjit Singh Lamba, Chair- OPPI Technical & Supply Chain Committee and Managing Director, Eisai Pharmaceuticals India says, “FDA initiated quality by design (QbD) and process analytical technology (PAT) principles in 2003 with the purpose of building quality into the product right from the beginning of manufacturing. The traditional quality by testing (QbT) approach tests product quality by checking it against the approved regulatory specifications at the end of manufacturing stream.”

Over the past few years, regulators have encouraged manufacturers and indeed mandated that testing should start as early as possible in the product development phase. The International Conference on Harmonisation (ICH), describes the principles of quality-by-design (QbD), in ICH Q8 (R2) as “a systematic approach to development that begins with predefined objectives and emphasises product and process understanding and process control, based on sound science and quality risk management.”

As Lamba puts it, “QbD principles promote innovation and continuous improvement of the product. Knowledge-based commercial manufacturing ensures enough regulatory flexibility for setting specifications and post approval changes.”

As part of this approach, he says that product and process are designed using innovative risk-based techniques to meet predefined quality objectives thereby satisfying the most critical patient needs and regulatory requirements at low cost. Innovative approaches such as quality management programmes, process capability measurements, Six Sigma, lean manufacturing and continuous improvement programmes can be adopted to improve the quality of pharma products. Understanding the relationship between critical material and critical process attributes culminates in process control and continuous improvement.

Impact of low quality ingredients

Ajit Singh

Ajit Singh, Chairman, International Pharmaceutical Excipients Council of India (IPEC India) and ACG, reminds us that excipients can be the major constituents of pharma dosage forms in comparison to the API. Thus they are functional and impact the performance of the finished drug product including drug delivery and stability.

Suresh Pareek, Managing Director, Ideal Cures too stresses this fact, saying that excipients can make up more than 90 per cent of the dosage form and thus can no longer be considered inactive.

It follows that quality of excipients have a direct impact on patient health. “Not ensuring effective quality standards of excipients used in manufacturing medicine, poses a great risk to patient safety. The impact of each excipient on the API must be studied as excipient quality impacts stability, quality, availability, tolerance and much more,” says Pareek.

There have been many incidents across countries, when counterfeit or poor quality excipients in medicines have impacted patient safety, with some unfortunately resulting in fatalities.

Singh recalls several incidents associated with excipients that led to the discussions that excipient pedigree must be known. For instance, incidents in Haiti, Panama and Bangladesh where substitution of the excipient glycerol by counterfeiters had lethal consequences.

Similarly, in the 2006 Panamanian case, a Chinese factory was found to have exported diethylene glycol mislabelled as the glycerol suitable for use in medicines. The result was some 100 fatal poisonings.

The issue has been a longstanding one. Singh mentions a case from 1990, when cough syrup contaminated with solvents led to 47 reported deaths in Nigeria.

Closer home, paracetamol syrup contaminated with diethylene glycol resulted in 236 reported deaths in India and Bangladesh between 1986 and 1998.

A similar case of diethylene glycol poisoning led to 88 reported deaths in Haiti in 1996. Excipients cause havoc in related sectors as well, with the case of melamine contamination in baby foods manufactured in China making international headlines.

Suresh Pareek

The affected companies include some of the biggest names in the business. As an illustration, Pareek cites cases related to three companies – Sun Pharma, Forest Pharmaceuticals and West-Ward Pharmaceuticals – which initiated recalls in 2014 due to dissolution problems related to excipients.

Enforcement reports of the US FDA show that Sun Pharma’s Caraco Pharmaceutical Laboratories subsidiary initiated a recall of more than 40,000 bottles of ventafaxine hydrocholoride extended release tablets, due to failed drug release dissolution specifications. The recalled tablets were manufactured at Sun Pharma’s facility in Gujarat.

Similarly, Forest Pharmaceuticals initiated a recall of 92,544 bottles of Bystolic (nebivolol) tablets due to failed stage III dissolution testing. West-Ward Pharmaceuticals recalled more than 26,000 bottles of TB drug isoniazid tablets, which failed dissolution specifications, as stability lots did not support dissolution past the 36-month time point.

Such recalls are by no means restricted to US jurisdiction. Another example cited by Pareek, dated as recently as November 28, 2017, concerns an alert posted by the UK regulator Medicines and Healthcare products Regulatory Agency (MHRA). Takeda UK issued a company-led drug alert for one batch of Calcichew-D3 500mg/400 IU Caplets due to traces of a non-approved excipient.

A brief description of the problem stated that the concerned batch was being recalled because ‘the product has been found to contain traces of a non-approved excipient (a Patchouli-like oil) which has inadvertently been added to the lemon flavouring used in the manufacture of the tablets. Takeda has no reason to believe that the non-approved substance poses a significant risk to public health.’

Never too early for QbD

Early stage testing may seem logical but pharma companies traditionally tested only the finished final product, or designated testing to the later part of the production process. By this stage, it was too late to make changes and save the batch. And worse, late stage quality testing merely detected poor quality product but did nothing to detect the case of the failure or prevent future non compliance.

Illustrating how this approach works at the drug formulation development stage, Lamba outlines four basic steps that formulation scientists need to follow to implement QbD principles as defined in ICH Q8 (R2). The first crucial step in any formulation development is to understand product profile which is called as quality target product profile (QTPP) in terms of regulatory. Once QTPP is identified, the second stage requires the formulation scientist to define what the ‘potential’ critical qualities are attributes of the product (critical quality attributes – CQAs).

The third stage involves designing and implementing a risk assessment control strategy to link raw material attributes and process parameters to CQAs. Once the risk assessment control strategy is implemented, the fourth stage kicks in, which involves managing the product lifecycle within the design, this becomes the basis for continuous improvement of the process.

Global guidelines like the ICH Q9 Quality Risk Management, ICH Q8 (R2) Pharmaceutical development and ICH Q10 Pharmaceutical Quality systems are considered crucial to the product development stages, according to Lamba.

Singh makes the point that all the stages in the product development lifecycle, from conception, product planning, design review, prototype preparation, pilot production, mass production and finally sustenance support, are interlinked system requirements for the designing, development and production. Thus, “the cost to fix problems increases exponentially as the project progresses further.”

Explaining further, he says, “An ill-conceived product definition can lead to defective product design and ongoing operational problems during drug product manufacture. Each drug product is composed of an API, as well as several excipients, that serve to aid in the performance and manufacturability of the API in the drug product. Although it is clear that variability in the API will have an impact on the performance and manufacturability of the drug product, it is also now important to consider that, variability in the excipients may also impact the performance and manufacturability of the drug product. The level of impact of excipient variability will depend on the drug product, its formulation and the manufacturing process.”

The cost of QbD …

The general perception is that rules and regulations add to the cost and time taken. Hence introducing regulations always faces resistance and implementation challenges. But not if they are implemented from Day One of a project.

Lamba stresses that there are many benefits of QbD at formulation research and development (fR&D) stage, which are crucial to deliver a cost efficient approach for delivering high quality drug substances and drug products consistently.

For one, the product is developed /built considering the customer (patients’) need. Secondly, a robust process is developed as it focusses on control strategy rather than testing.

Thirdly, the overall development is systematic and multivariate experiments are conducted to understand the process and product which establish a design space. The fourth benefit is that the process is adjustable within the design space, which is not the case with a fixed process.

And lastly, the product life cycle is managed as a preventive action rather than reactive problem solving.

It boils down to managing cost versus risks. Proper implementation of QbD can in fact lead to savings in terms of both time and money. Explaining this, Lamba opines, “The proper risk assessment is key to avoid more experimentation, testing and documentation. If the control strategy and design space is well established, then there will definitely be benefits considering the product scale-up and commercialisation which can eliminate the risk of product failure and consistency in the manufacturing.”

As he reasons, a QbD approach can help avoid delay in the process validation. The current scenario requires more efforts during the process validation stage which can be minimised by using QbD. The process can be changed within the design space (PAR values) which helps in avoiding updation of regulatory filings, variations and follow-ups, time and money.

… and how QbD cuts costs

Lamba gives a classic example how having a well defined design space can be helpful for continuous manufacturing and to provide an un-interrupted supply of quality product at a competitive cost structure.

He refers to a product being manufactured at Eisai Pharmaceuticals India for the Japan market. “During commercial manufacturing, we observed extended drying time for intermediate stage which resulted in a delay of about seven days in the batch cycle. This is (a) huge (delay) considering the product demand and supply.”

This observation required a change in the input quantity of solvents in the process. “When we approached the regulator, they accepted this change as very minor change. This is because we had considered a change within the design space and it was well mentioned and explained in the filing dossier.”

In fact, not following QbD would result in significantly higher costs in the long run. As Singh puts it, “Quality issues in a product at the field level would have a very high cost to resolve the problems, these problems result in costly rework, lot rejections, product recalls and quality investigations for the manufacturer and also result in loss of credibility, low customer satisfaction, and potentially lead to plant shut downs. This demonstrates a strong need for quality by plan and not by chance. Hence under the QbD paradigm even though costs are involved, pharma quality for generic drugs can be improved by understanding and controlling formulation and manufacturing variables.”

Singh cites a few of many reports to highlight the fact that excipient variability is inevitable (See Box: Excipient variability and impact on final product). Emphasising that its influence on product quality needs to be accounted for, he says this is best done by the development of robust formulations since it is rarely successful to try to control the variability through use of tighter specifications which could have a significant impact on the availability of supply.

Excipient variability and impact on final product

Barra et al. examined the physiochemical properties and lubricity of 13 lots of Magnessium stearate (MgSt) from three different vendors. They found that MgSt supplied by different vendors are unlikely to have the same physical properties, and variations in physical properties can be expected within lots supplied by the same vendor. The mean particle size of MgSt was found to be the key factor influencing its lubricant efficiency. The crystalline structure was also found to influence the compaction characteristics of the formulation, but with less impact than the mean diameter for the systems studied. In addition, Hamad et al. found variability in physical properties of different types of MgSt and these differences can influence tablet ejection force.

Gamble et al. reported on the batch-to-batch and vendor-to-vendor variations in the solid-state characteristics of anhydrous lactose and the subsequent impact of these differences on functionality. The intra-vendor variability was generally low, although some batch-to-batch variation was observed. Not all the measured inter- and intra-vendor variations in powder properties were observed to have a significant impact on the compression/ compaction characteristics.

Albers et al. examined three lots of MCC type 101 from five different manufacturers for a total of 15 batches. The 15 batches showed different tableting behavior, and analysis of variance confirmed that the variation between different manufacturers and different batches of one manufacturer were statistically significant.

Studies done by Doelker et al. and Williams et al. examined the impact of different MCC suppliers and within-grade, lot-to-lot variability on tableting properties. It was found that variations exist between various sources and sometimes between lots from the same suppliers. Those variations had a significant impact on tableting indices or tablet product properties.

(Source: Ajit Singh, Chairman IPEC India & ACG)

Thus, he reasons that development of robust formulations avoids future hurdles of continued production, helps in the understanding of concerns during manufacture and enhances ability to appropriately attend to trouble shooting. This process also helps in answering any type of queries from FDA reviews.

Will guidelines …

Such incidents highlight the importance of monitoring the quality of excipients as well as APIs. As Singh of IPEC India & ACG stresses, “Quality of the excipient is critical to the drug product and this has not been a major focus of regulators in the past. Increase in type of dosage forms, use of multi-functional excipients, upgrading industrial grade by testing it, are some of the reasons that have attracted attention to excipient quality.”

A vital part of a drug formulation scientist’s concerns about implementing QbD principles as defined in ICH Q8 (R2) is identifying and putting in place a secure raw material supply chain. Excipient manufacturers have stepped in to smoothen this process.

As Singh puts it, “Excipient manufacturers are proactive collaborators in identifying the critical material attributes (CMA) that may affect the product quality and manufacturing process and provide the necessary data to the pharma manufacturer.”

Policy makers too have taken steps to plug these gaps. For instance, Singh points out that the Directive 2011/62/EU (Falsified Medicines Directive) mandates the Manufacturing Authorization Holder to conduct excipient risk assessment and ensure appropriate quality and GMP from the excipient manufacturer.

Pareek too cites three important latest global guidelines for excipient risk assessment and ensuring product safety: The EMA Guidelines on Excipient Risk Assessment (2015), IPEC-PQG (Pharmaceutical Quality Group) GMP Guide 2006 and IPEC GDP Guide 2006, which are broadly recognised as industry standards and are voluntarily applied to excipient manufacturing and distribution and the the NSF/IPEC/ANSI 363 standard for pharma excipient GMPs provides a harmonised and comprehensive set of criteria for the quality management systems used in the manufacture of pharma excipients worldwide.

… and third party audits …

Today, excipient manufacturers have a well defined path towards compliance via EXCiPACT, a non-profit organisation, that owns and manages oversight of an independent, high quality, third party certification scheme.

The EXCiPACT website reportedly lists over 60 certificate holders based across 15 countries, ranging from major international suppliers with multiple sites, to single site, smaller suppliers in Asia, Europe, the Mid-East and North America. Manufacturing facilities of both ACG and Ideal Cures are listed as EXCiPACT Certificate Holders.

Such a process, though not perfect, serves the purpose of both excipient suppliers as well as pharma companies.

Justifying the need for third party audits as the best solution, Singh reasons, “Pharma companies are experiencing an increase in regulatory demands for ensuring raw materials – including excipients used in the finished drug product are safe, high quality and sourced from qualified suppliers following appropriate GMPs. This has led to an increase in audits of excipient facilities by pharma companies and excipient manufacturers are in turn experiencing increase in demand of related documentation for ensuring their site and product meet the required regulations. It is difficult for both the pharma and excipient industry to cope up with this demand. Hence an audit by a third party who is independent of both the excipient supplier and customer would resolve any conflict of interest.”

Pareek of Ideal Cures too endorses this approach saying, “A practical approach, third party auditing helps to overcome a number of obstacles such as import related issues, unexpected delays, multiple locations for audit, insufficient knowledge of in-house auditors regarding chemicals etc. Such certification schemes help bring about harmonisation in standards across the globe, bringing it all together under one body.”

… help the two to tango?

The tricky question is: who is to blame for a pill that kills? The patient knows the pill by its brand name, while the several ingredient manufacturers, remain faceless on the chemist shelf. Assuming regulators can trace the erring inputs to the source, can excipient suppliers be brought to book?

It seems that excipient manufacturers, at least the more established ones with their own brand image to protect, are willing to share this responsibility.

As Singh says, “Although it’s the responsibility of the drug manufacturer to ensure safety of the drug, it is the excipient manufacturer’s responsibility to adequately control the excipient manufacturing process to assure consistent excipient conformance to the agreed specifications and GMP guidelines.”

This seems to be the consensus in the industry. While Pareek opines that it is the responsibility of the pharma dosage form manufacturer to ensure the safety of their drug product and the excipients used in the formulation, he also concedes to his responsibility as an excipient manufacturer.

As Pareek explains, “While the pharma formulator is primarily responsible for identifying the particular physical characteristics needed, it is the responsibility of the excipient manufacturer to adequately control the excipient manufacturing process to assure consistent excipient conformance to the agreed specifications.” If the excipients are not in line with the proposed specifications, he opines that the excipient manufacturer should reject the lot and not release it in the market.

Citing from the IPEC-Americas and IPEC Europe Guidance document – “Qualification of Excipients for use in Pharmaceuticals,” Singh lists three important criteria to be met for any excipient to comply as a pharma grade excipient.

Firstly, excipients must be manufactured under appropriate cGMP conditions (Joint IPEC / PQG Good Manufacturing Practice Guide for Pharmaceutical Excipients 2017).

Secondly, in order to label an excipient as compendial grade, regardless of the pharmacopoeia, all monograph and appropriate General Chapter or Notices requirements ordinarily must be met. Thirdly, traceability along the entire supply chain must be established and verified.

Compliance beyond pharma

As Singh points out, the excipient supplier’s business is in diverse industries like foods, personal care and dietary supplement products and pharma being a small share amongst them.

“However, if an excipient supplier intends to sell a product to the pharma industry then it has to share some responsibility towards the safety of the drug products. For this, it is necessary to first understand the intended functionality of the excipient in the drug product and carefully agree to the quality specification with the drug manufacturer. A quality agreement is necessary. The excipient manufacturer should remain aware of new regulations, compendial tests affecting their products and ensure compliance to them.”

Harmonisation with national guidelines

India is home to many excipient manufacturers land excipients are exported to all major geographies. Thus India’s pharma sector regulators, the CDSCO and DCG(I), can play a huge role in monitoring quality of excipients.

Singh emphasises that first and foremost, there has to be a dialogue between the Indian regulators and excipient industry. “There has to be a serious initiative to understand how excipients are controlled in highly regulated regions like the US and EU. Simply controlling excipients like medicines should be avoided, instead a more practical approach needs to be developed. IPEC India can play a vital role in providing guidelines for excipients that India FDA can adopt.”

As excipient manufacturers cater to multiple end user industries, like food as well as pharma, they will have to coordinate with multiple regulators. Highlighting this aspect, he points out, “There also needs to be an understanding between CDSCO and FSSAI which excipient manufacturers will need to approach due to the usability of their products in both pharma and as food additives in foods. CDSCO and FSSAI can initiate an activity that can make regulation more adaptable for excipients – have clear guidelines for them rather than simply follow the drug or food/ nutraceutical regulations. Experts from IPEC groups can help develop this or can be advisors or consultant to CDSCO and FSSAI develop this.”

And thirdly, Singh highlights the role of the Indian pharmacopoeia and informs that IPEC India is also collaborating with the Indian Pharmacopoeia Commission to update/harmonise existing excipient monographs and add new excipient monographs.

Pareek recommends that the CDSCO and DCG(I) will need to focus on core excipient manufacturers in same way as is done for drugs formulations and APIs. “The local health authorities shall examine and audit the excipient manufacturers in accordance to the pharma GMP norms or the IPEC guidelines, that are very apt for the excipients. The process ingredients, i.e. the intermediates used in the manufacture of excipients as well the processing stages such as chemical synthesis, extraction, purification etc. should be verified and understood for better improvements. The local health authorities will then need to collaborate with the global regulators (US FDA and European regulators/ TGA) and accordingly, our norms or specifications / process manufacturing steps should be made stringent so as meet with the global regulatory needs.”

To facilitate this process of harmonisation with global norms, Pareek suggests that the health authorities should have a panel team, who should work jointly with the global regulators and should bring up a common conclusion on excipient regulations.

Global guidelines for excipient risk assessment

Directive 2011/62/EU (Falsified Medicines Directive)
The EMA Guidelines on Excipient Risk Assessment (2015)
IPEC-PQG (Pharmaceutical Quality Group) GMP Guide 2006
IPEC GDP Guide 2006
The NSF/IPEC/ANSI 363 standard for pharmaceutical excipient GMPs

Sharing responsibility

To conclude, Pareek stresses that excipient manufacturers and pharma companies need to have a shared responsibility of ensuring excipient safety. He refers to reports that regulatory bodies in the US, EU, and Japan, as well as those in the BRICK (Brazil, Russia, India, China, and Korea) countries, are modifying existing and/or introducing new regulations for finished pharma products that specifically address excipients, either directly or indirectly. He emphasises that discussions have to occur between both parties to clearly understand the impact of every excipient used on the API.

This focus is good for the excipients sector as only bonafide suppliers will survive the scrutiny. Hopefully, this will result in a more secure supply chain and ultimately safer medicine for patients.

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