1. Introduction
Manufacturing excellence in the Pharmaceutical and Biopharmaceutical industry is a hallmark of Ireland’s success in the sector. This sector is constantly driving growth, and Ireland has seen continued capital investment averaging €1 billion per annum over the last 10 years [
1]. There are over 85 pharma companies in Ireland, with 9 of the world’s top 10 pharma companies operating in Ireland. Ireland is now the largest net exporter of pharmaceuticals in the EU, accounting for over 50% of all exports from the country [
2]. The sector employs more than 30.000 people in Ireland [
3]. At the EU level, Pharmaceutical manufacturers contributed €37 billion in 2019, and the sector provided 800,000 direct jobs and a €109.4 billion trade surplus [
4]. The biggest export markets for Irish Pharma products are Europe and the USA, receiving 36% and 30% of Irish pharma exports, respectively [
5].
By their very nature, pharmaceutical medicines and drugs are dangerous if misused or prescribed incorrectly and can have many side effects, including fatalities. Regulation affects every aspect of the pharmaceutical sector, including pre-marketing development, marketing authorisation, manufacturing, and post-marketing activities [
6]. The manufacturing of pharmaceutical products is thus subject to stringent regulatory strictly controls by authorities to ensure product safety, Quality, and efficacy. In addition, manufacturers must conform to the regulatory requirements of the geographical region in which medicines and drugs are being manufactured and the regulatory regimes to which they are being exported or marketed for use [
7,
8]. The industry is one in which revenues are decreasing because of competition from generic alternatives [
9], while the costs of R&D are rising and competition is increasing [
10]. Hence the Pharma industry is increasingly adopting CI as a means of improving efficiency and reducing costs.
Dale [
11] define continuous improvement as “
the means of improvement to people and process performances needs to be continually sought and monitored”. The implementation of continuous improvement methodologies must consider the development of a culture for continuous improvement, which aims to eliminate waste in all processes, involving all employees, without necessarily having a significant financial expenditure [
12]. Many continuous improvement methods are utilised by organisations in all types of industry, with Lean, Six Sigma, and Lean Six Sigma (LSS) evolving as the CI methodologies of choice in recent years [
13].
While CI methodologies have been deployed widely in many organisations, the application in highly regulated industries such as the Pharmaceutical industry is not as researched or studied as in other sectors [
13,
14,
15,
16,
17]. Examples of some large Pharma companies which have Lean programs include Astra Zeneca, Johnson & Johnson, and Pfizer [
18].
There have been some studies on Lean application in Pharma [
14], for example, Pharma industry readiness for Lean [
19], and how Lean can be practiced in a Pharma environment [
20]. Pharmaceutical companies are secretive by nature and are cautious about releasing any information that may put them at a disadvantage to their competitors [
21]. Several studies on CI in the highly regulated and comparable medical device industry have highlighted the regulated nature of the industry as a barrier to CI [
20,
22,
23]. Furthermore, although organisations have widely implemented CI, sustaining the momentum of CI activities have been a challenge [
23]. This research contributes to a gap in published literature by investigating the critical failure factors (CFF’s) and benefits for CI methodology deployment and identifying the types of CI methodologies utilised for deploying CI in the Irish Pharmaceutical sector. Further, the study also investigates if the highly regulated nature of the pharmaceutical sector is an additional CFF and barriers to embracing CI. This research will also explore the extent of continuous improvement methods such as Lean, Six Sigma and Lean Six Sigma within the industry and the type of CI tools utilised. The authors are asking the following research questions:
What are the CI methods and tools utilised for CI in the Irish Pharmaceutical industry?
What are the drivers and benefits for use of CI within the Pharma industry?
What are the CFF’s for deployment of CI in the Irish Pharma industry?
Does the highly regulated nature of the Irish Pharmaceutical industry pose a unique and significant barrier to CI methodology deployment and culture?
The remainder of the paper is as follows;
Section 2 describes the literature, followed by research methodology in
Section 3. Next, the results are presented in
Section 4, followed by a discussion and implications in
Section 5. Finally, the conclusion, limitations, and scope for future research are outlined in
Section 6.
4. Results
The respondents were asked basic questions about their location (which was distributed in Ireland) and industry type, whether pharmaceutical or biopharmaceutical. The analysis plan is detailed in
Figure 2, given below.
As shown in
Table 1, the respondents came from a wide range of functional areas within their organisations. These functional areas contribute to the successful manufacturing and product distribution associated with pharmaceutical manufacture. The majority of respondents, nearly one in four, worked directly with the manufacturing floor (24%) as pharmaceutical or biopharma production operators or supervisors. The functional areas that support pharmaceutical production included manufacturing or process engineering (14%), operations quality (9%), validation engineering (9%), and QC laboratories (9%), followed by continuous improvement and supply chain/logistics functions at 8% each. Thus, there was a representative selection of participants from all functional areas within a manufacturing facility. Unfortunately, not all functional support areas, such as HR, pharmacovigilance, and other support functions, such as R&D and supplier quality, were as widely represented as those very involved with direct pharmaceutical GMP production lines. However, continuous improvement methodologies tend to be traditionally more strongly associated with the manufacturing floor, so there was a good representation of respondents familiar with CI methods.
Respondents were also asked to select from a range of possible generic or pharmaceutical quality standards or regulatory systems that they were certified to or in compliance with (
Table 2). Respondents could select one response or all that applied from a range of examples, including 21 CFR part 211 or part 10, ISO 9001:2015, or ICH systems.
As the majority of Irish pharmaceutical companies export into Europe and are licenced to export into the USA, they are often in compliance with both European regulations and U.S. FDA regulations and other global regulatory regimes depending on their export markets. Respondents were given options related to the International Standard Organisation (ISO) standard for quality management systems, which can be applied to any organisational product or service, known as ISO 9001:2015. Other choices listed included the FDA Code of Federal Regulations (CFR) current good manufacturing practice (cGMP) regulations for finished goods pharmaceuticals (21 CFR Part 211) as well as the FDA CFR cGMP regulations for manufacturing, packing, or holding of drugs (21 CFR Part 210).
The European Medicines Agency publishes scientific guidelines on human medicines that the International Council harmonises for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The EMA requires that pharmaceutical manufacturers follow the ICH Guideline Q10 on Pharmaceutical Quality System (PQS) requirements in relation to their QMS. There is also a guidance called the ICH Q7 Good manufacturing practice for active pharmaceutical ingredients (API). Regional GMP requirements, the ICH Q7 Guideline, “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients”, and ISO quality management system guidelines form the foundation for the ICH Q10 PQS system [
41].
While the FDA, the EMA and ICH have many guidelines related to drug development, manufacturing and product release, only the relevant guidelines related to GMP and QMS’s were included in this study. As a result, some pharma organisations may have been certified to comply with more than one of the QMS or GMP guidelines, regulations or standards outlined in
Table 2, depending on their export markets. Compliance to both FDA GMP, the aforementioned ISO standard, and the ICH Q10 guidance can help an organisation provide superior products, processes, and invaluable customer service. This will result in a safer and healthier drug-product pipeline and an improved financial bottom line for the industry [
54].
Nearly one in three of the respondents (28%) stated that they were in compliance with 21 CFR part 211 the US FDA regulations for cGMP for finished pharmaceuticals, with one in four or 25% stating they had been certified to ISO 9001:2015 and a further one in four or 25% stating they adhered to the ICH Q10 PQS. As ISO 9001 certification is the most widely utilised standard for any generic type, it is implemented widely but is not required by global regulatory pharma authorities. However, certification to ISO 9001:2015 demonstrates that a specific set of criteria for the quality management system has been created, maintained, and is supported by top management.
In relation to the types of CI methodologies utilised within the Irish pharma industry, respondents were questioned on “which CI methodologies are you applying within your pharmaceutical organisation?” As demonstrated in
Figure 3, 51% of respondents indicated that they utilised Lean, Six Sigma, and LSS, with 29% stating they used only LSS. In total, 97% of respondents stated that they used CI methodologies. Only 3% of respondents stated that none of the aforementioned CI methodologies are utilised in their organisations. Those respondents are likely based in non-manufacturing-related functions or support functions that may not regularly use CI methods.
The internal reasons for using CI in Irish pharma organisations were the respondents’ next question. The respondents were asked to rate whether productivity, customer focus, quality, regulatory, and safety reasons were of a high, moderate, or low driver or not a driver at all for implementing CI in their organisations.
Productivity was seen as a high driver at 59% and a driver at 33% -there was an overwhelming consensus that a Productivity (92% combined) focus drives CI in Irish Pharma. A Quality focus was nearly as high a driver of CI deployment as Productivity, with 55% of respondents stating Quality was a high diver and 28% stating that Quality was a driver (83% combined). Both Productivity and Quality are more or less equally high as priorities for deploying CI initiatives. However, Customer focus, Financial and Safety were ranked as high drivers (all at 43%). This suggests that while Productivity is more important to Pharma organisations than Quality, customer and safety is also high on these organisations priorities. Generally, the most common driver for pharmaceutical companies to adopt Lean is improving overall manufacturing Productivity and efficiency [
45].
A regulatory focus was seen as the lowest-ranked area in the high driver of CI methodology category at 28% but was the highest rank driver in the “driver” category at 35%. This was a surprising finding given that the industry is so highly regulated to provide safe, quality, risk-free products, which are vital inpatient and general public treatments and can result in life-or-death situations. As these organisations adhere to so many regulations driven by external government authorities to ensure safe products are manufactured, it would be assumed that regulatory focus drove CI and not productivity. The results are outlined in
Table 3.
The next question asked was how integrated they felt that CI methodologies were in areas of their Quality Management System and within other departmental functions and systems. Respondents indicated that CI tools were “very integrated” into the following areas in order of ranking: (1) Corrective and Preventive Action System (CAPA) (49%), (2) deviations (Non-Conformance) processes (46%), (3) internal and external audit systems (44%), and (4) pharmacovigilance systems (33%). These four aforementioned areas also had a high “integrated” result. Only the management review process, the supplier quality CA process, and design assurance processes were ranked the lowest in having CI methods “very integrated” into their QMS systems. However, even these three areas had relatively high combined “very integrated” and “integrated” results of 49% (management review process), 37% (supplier quality CA processes), and 31% (design assurance), suggesting that there was still a very high integration of CI methods within these areas even if CI was not as highly integrated there as in other areas. These results suggest a strong focus on CI methods and systems integrated throughout the pharma product lifecycle.
Management and leadership commitment is critical CSF’s for CI [
50,
55]. Almost 1 out of every 2 respondents (49%) felt that CI was very integrated and integrated in terms of being reviewed in the management review process. This suggests a reasonably strong commitment from Pharma leadership to improve their processes continuously.
The results are outlined in
Figure 4. While Pharmaciovigilance systems are utilised to ensure product safety in the public domain, Customer Complaints and sourced supplier ingredients and components performance data can provide an important source of information and failure modes for feedback and input to CI programs. However, there were limited respondents from the supplier quality function in the survey, so perhaps the respondents’ knowledge of the supplier quality systems may not be substantial.
As all regulatory authorities require manufacturers to show evidence of some corrective and preventative action or improvement system within their QMS, it is not surprising that CI tools are considered very integrated into all areas of the Irish Pharma manufacturers QMS’s and PQS’s. The purpose of the corrective and preventive action subsystem is to collect information, analyse information, identify and investigate product and quality problems, and take appropriate and effective corrective and preventive action to prevent their recurrence.
As all regulatory authorities require manufacturers to show evidence of some corrective and preventative action or improvement system within their QMS, it is not surprising that CI tools are considered very integrated into all areas of the Irish pharma manufacturers QMSs and PQSs. The purpose of the corrective and preventive action subsystem is to collect information, analyse information, identify and investigate product and quality problems, and take appropriate and effective corrective and preventive action to prevent their recurrence. Moreover, a sizeable % of respondents were from the manufacturing area functions and the quality function and so would be more familiar with the CAPA, deviations, and audit systems processes than other more non-manufacturing-related support functions.
Leadership plays an important role in strategy, particularly CI deployment and adoption [
48,
49].
Lean programs aim to optimize global capacity and inventory while ensuring an uninterrupted supply of needed medicine [
56]. The respondents were asked to pick the benefits of having CI in their organisations (
Table 4); the respondents listed the following benefits in order of preference (1) improved Productivity (25%), (2) improved product quality (23%), (3) achieved cost savings (14%). There seems to be almost equal importance placed on Productivity in hand with Quality. From the customer’s perspective, the fact that a pharmaceutical plant is running with surplus capacity should have little consequences in the short term. The product will still be delivered on time, at the right Quality, and according to cGMP, but the plant with surplus capacity available has higher operating costs [
18]. Thus it is more understandable that the benefits of CI related to customer needs and wants were ranked extremely low as if the plants have surplus capacity, customer needs are met, but operating costs are more of a priority. Cultural aspects of CI benefits such as teamwork and communication also scored very low.
A multiple-choice-type-answer question was asked on the CFFs for CI based on the literature, and respondents were asked to pick five CFFs. The top CFFs to CI (
Figure 5) was seen as (1) resistance to a CI culture change (12%), (2) lack of training and education (10%), (3) poor communication about CI from senior management (9%), (4) lack of resources (financial, technical, human, etc.) (8%), and (5) a lack of awareness of the need for LSS and its benefits (8%). Fear of extra regulatory work, e.g., validation as a result of CI projects, also features in the top six CFFs.
The Senior Management and leadership role features as a recurring theme in the top 10 of the questionnaire responses in terms of poor communication about CI from senior management (ranked #3), lack of leadership skills and vision (ranked # 8) and lack of top management attitude and commitment (ranked # 10). This support can be a serious CFF for any CI initiative [
47].
Moreover, the finding that only 20% of respondents felt CI reviews were very integrated into the management review processes and systems supported this finding even if a further 29% thought it was integrated. As support for CI and training comes from leadership support and direction, as does enabling CI culture, it is not surprising that lack of training and education and resistance to culture change is the second- and third-ranked CFFs after poor communication about CI from senior management. A lack of resources can also be attributed to a lack of support from leadership and an already heavy compliance workload.
The next question asked was, “Which of the following CI tools are utilised in your organisation, or are you aware of it as being utilised (please tick all that applies to your organisation)?” The respondents were provided with several Lean and Six Sigma tools from which to choose and aid in their responses (
Figure 6). The top five tools utilised according to the respondents were (1) C&E, (2) 5 Whys, (3) 5S, (4) process mapping, and (5) brainstorming and FMEA (equal) in order of ranking. The least utilised or recognised tools were Hoshin Kanri (strategic top-down, bottom-up planning), hypothesis testing, and Hejunka (Level scheduling). As Hoshin Kanri and Hejunka are the original Japanese Lean terms, some respondents may not recognise these, or they may be utilised under different names if they are being used.
Just under 100% of respondents (77) stated they had utilised Cause and Effect analysis or were familiar with it. Over half of the tools listed in the survey were utilised by over 50% of respondents organisations, with several of the remaining tools utilised by between 25% and 30% of respondents. This suggests that CI tools are familiar to these organisations; people have been educated about their use and are familiar with them. As 97% of respondents stated that they utilised CI methodologies within their organisations (Lean, LS, SS), this would back up this result of high awareness and use of CI tools.
A question was asked concerning this to establish if a highly regulated environment is a barrier to continuous improvement programs in Irish pharma. Respondents were given a simple option to answer “yes” or “no” to the question that regulated environments were a barrier to CI. More respondents answered “no” (55%) to this question and stated that regulatory compliance or regulations were not a barrier to CI in Irish pharma organisations. However, there was a decisive “yes” vote (45%) in response to the question (
Figure 7). The results suggest some evidence to the argument that a highly regulated pharma environment can stifle CI initiatives.
This correlates with the literature which has stated that Pharmaceutical manufacturers are reluctant to change processes that are confirmed and validated and accepted as compliant [
13,
16,
18].
Respondents who answered “yes” that they believed that a regulated pharma environment was a barrier to CI deployment and progress were asked another question in relation to specific barriers to CI using a Likert scale (
Table 5). The “strongly agree” and “agree” answers to this question were high, as this question was only completed by the 45% of respondents who had answered that pharma regulations were a barrier to CI. The top reasons highlighted in order of the “strongly agree” rankings by those who felt there were barriers to CI in regulated industries were, in order of ranking: (1) fear of extra validation activity (44%), (2) a compliance versus quality culture (42%), (3) a regulatory culture within the organisation of being “safe” (42%), and (4) fear of extra regulatory submission workload (42%). The combined “strongly agree” and “agree” vote for all of the issues mentioned above was between 70% and 89%, which indicates that the regulatory environment was deemed a considerable barrier to CI.
A total of 44% of respondents strongly agreed, and 31% agreed that fear of extra validation activity is a barrier to CI. “A fear of extra submission workload” as a barrier to CI, while only having a low “strongly agree” vote at 42%, had a 31% “agree” vote agreeing that it was a barrier factor for CI. The “CAPA system seen as unwanted extra work,” having a low “strongly agree” vote of 14%, had the highest “agree” vote as a barrier to CI at 42%.
The barriers of having a “compliance versus quality” culture had a strongly agreement percentage of 31% and an agree vote of 39%, while a regulatory culture of being “safe” had a 42% strongly agree vote and a 47% agree with vote. These two barriers are reflective of a regulatory focus that could stifle CI.
While external audit preparation can be very time-consuming, a heavy external audit schedule as a barrier to CI had a very low “strongly agree” vote of 11% compared to other barriers offered. However, it had a high 25% of “agree” votes.
“CAPA was seen as unwanted extra work” while not in the top “strongly agree” barriers to CI had a strongly agree vote and an agree vote of 14% and 42% that it was a barrier to CI. CAPA’s are seen as time-consuming and extra paperwork [
57]. A global medical device manufacturer, Medtronic stated that they spend “about
$150m on CAPA” [
58].
Interestingly, CI, being seen as a quality department initiative, had the highest disagree and strongly disagree vote at 36% and 11%, respectively, suggesting that CI was generally owned by more than just the quality function. This suggests a positive CI culture across the organisation. This finding also correlates with the previous results that 97% of the respondents stated CI methods are being utilised in their organisations and that there was a high familiarity and knowledge of CI tools.
5. Discussion and Implications
This research has concluded that Irish pharma has adopted and integrated CI methods, with CI methods being utilised and deployed in 97% of participating manufacturers. The top five tools used for CI according to the respondents were (1) C&E, (2) 5 Whys, (3) 5S, (4) process mapping, and (5) brainstorming, in order of ranking. These tools would be deemed very traditional basic tools, suggesting usage and engagement in fundamental problem solving and CI. On the other hand, some more complex CI tools, like Hoshin Kanri, Hejunka, and statistical-based hypothesis testing, were the least utilised or recognised tools cited by respondents, suggesting that management could be doing more to train and educate on CI within their organisations.
In terms of the benefits of CI in Irish Pharma organisations, (1) improved productivity, (2) improved quality, and (3) achieving cost savings were highlighted as the top three benefits.
CI tools were “Very Integrated” into the following areas in order of ranking: 1. Corrective & Preventive Action System (CAPA) (49%), 2. Deviations (Non-Conformance) processes (46%), 3. Internal and External Audit systems (44%), and 4. Pharmacovigilance systems (33%). This suggests a high integration of CI methods and problem-solving tools into the PQS and QMS. This demonstrates efforts to drive CI practices into the regulatory process. The ICH has also tried to focus on a strong CI approach via ICH 10 and ICH 12 [
41,
44].
The findings of this research found the top CFFs to CI were viewed as (1) resistance to a CI culture change, (2) lack of training and education, (3) poor communication about CI from senior management, (4) lack of resources (financial, technical, human, etc.), and (5) a lack of awareness of the need for LSS and its benefits.
Fear of extra regulatory work, e.g., validation as a result of CI projects, also features in the top six CFFs. This CFF is unique to regulated industries and would not have featured in other studies on CFFs for CI in industry.
A total of 55% of respondents stated that regulatory compliance or regulated environments did not stifle CI in their organisation, but 45% agreed that it did. The top six reasons highlighted in order of the “strongly agree” rankings by those who felt there were barriers to CI in regulated industries were: (1) fear of extra validation activity, (2) a compliance v’s quality culture, (3) a regulatory culture within the organisation of being “safe,” and (4) fear of extra regulatory submission workload.
The implications for this study are that it can inform continuous improvement programs in the Irish pharma and wider global pharma industry as to the challenges, CFFs, and barriers to deployment of CI. Apart from the findings on specific CFFs to CI that are common to all organisational types, there is some strong evidence that a regulated environment can be a further barrier to CI deployment in an organisation. Leadership teams can utilise this research to analyse their organisations and assess their readiness in terms of a regulatory environment for CI.. Within the academic community, this study is one of the first focusing on the barriers to CI within a pharma and regulated environment and should aid further study, research, and understanding of CI in regulated environments.