Pharma is generally viewed as having the most stringent regulatory requirements of any industry. Maintaining compliance with those requirements dominates manufacturing quality systems within pharma companies and their external production partners. In particular, regulations defining current good manufacturing practices (cGMPs) began taking shape in the mid-1970s and continue to evolve. However, significant changes to the manufacturing supply chain in the interim raise a critical question: Are the prevailing cGMPs sufficient to ensure companies are consistently manufacturing quality product?
Setting the bar: the birth of cGMPs
Some 50 years ago, there was a clear need to establish comprehensive standards for companies manufacturing pharmaceuticals, with the goal of ensuring the safety and efficacy of drug products. After all, in contrast with most other products, consumers have no way of assessing the quality of the drugs they ingest. A pill’s purity and effectiveness cannot be determined by its smell, coating or packaging.
And so, by the late 1970s, cGMPs were established to set a compliance bar for pharma manufacturers that — in turn — would provide an acceptable level of quality assurance. The U.S. Food and Drug Administration was initially the primary driver behind this initiative. Today, cGMPs are universally acknowledged, with most regulatory agencies working together as part of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The ICH Q7 Guideline specifically addresses cGMPs.
A dramatically shifting landscape
Of course, the world looks very different than it did when cGMPs were first conceived. The most obvious change is the technological revolution that has impacted just about every aspect of our lives. Within pharma, the most significant shift is that most manufacturing is now outsourced.
When cGMPs originated, pharma companies made drugs almost exclusively in their own plants, and the company’s logo on a product was all the assurance consumers needed regarding drug quality. Today, the same logo may appear on that product even if it was made by multiple outsourced production partners spanning several continents. Although the standards themselves define a comprehensive approach to ensuring plants have the necessary procedures, policies and manufacturing practices in place, two related factors must be considered:
- The cGMPs do not set any requirements for shop-floor technologies in an age when other industries make extensive use of measurement and automation.
- Verification that a company complies with existing cGMPs is achieved by periodic regulatory inspections. These inspections are generally rigorous, but there is no way to continuously verify that a company is following its procedures.
Together, these factors point to an industry that is not exploiting the capabilities of modern-day measurement, control and information management technologies. The current approach to quality assurance could be described as “minimalist.”
It is reasonable to expect that one of the world’s most critical industries would be using the best technologies available in manufacturing its products. However, drugs are still made largely in paper-based facilities — meaning batch records are paper documents with manually entered data and handwritten signatures. That limits the amount of information that can be readily accessed to verify production occurred according to the correct procedure.
A key omission in the information age
Again, the cGMPs are fairly comprehensive in detailing quality requirements for pharma manufacturers; some would argue they have served consumers well over the years. However, in this advanced technological age, demand for real-time data is ever-increasing. One might expect pharma quality systems to incorporate real-time monitoring capabilities to ensure cGMP compliance on a continuous basis. On the contrary, two decades into the 21st century, cGMPs make little mention of using advanced technologies to monitor and control manufacturing.
This omission represents a significant flaw, especially given the rise of outsourced manufacturing. No quality system can offer adequate accountability when it is underpinned by paper- and document-based processes — and manufacturers can fully satisfy regulatory requirements without the use of modern technologies. Pharma companies that outsource production have even less visibility into how closely their product manufacturing requirements are followed.
Different realities outside pharma
In contrast to pharma, consider the broad adoption of manufacturing technologies by industries that lack stringent regulatory oversight, but cater to increasingly more educated and demanding consumers. In the digital age, we rarely select a product or service before checking online user reviews. The internet has given us the ability to exhaustively research the opinions of others prior to making a purchase decision. Most consumer-facing companies must concern themselves not only with dissatisfied buyers, but also their influence over other potential customers. Arguably, this real-time “oversight” — conducted directly by consumers — is much more rigorous than the audit-based, regulatory environment in which pharma operates.
What’s more, product manufacturers typically compete in a highly price-conscious marketplace, meaning they must be very sensitive to manufacturing costs. These realities have forced manufacturers outside pharma to embrace advanced technology in order to:
- Exploit design and simulation tools to ensure “right first time” manufacturing
- Implement aggressive continuous improvement programs
- Deploy extensive automation on the shop floor
The goal is achieving maximum efficiency, predictability, reliability and, ultimately, the highest possible product quality.
How did we get here?
Multiple factors have prevented pharma manufacturers from advancing further technologically. As noted above, pharma faces much less intense consumer oversight and pricing pressure than other industries. cGMPs have not been updated to embrace 21st century technological capabilities. And so, most pharma manufacturing facilities remain paper-based, reflecting the focus on compliance that arose in the 1970s and continues to permeate the industry.
Even where manufacturing execution systems are deployed, they merely replicate paper documents in electronic form, commonly referred to as a “paper-on-glass” approach. Where control systems are deployed, they tend to be unit operation-focused — not deployed with the full end-to-end recipe-based approach defined in the ISA-88 Standard. A major impediment is that control system vendors have not made their solutions easy to use in a complex multi-product manufacturing environment with frequent changeovers.
In short, shop floor execution technologies often serve to reinforce the old, compliance-centered paradigm. Furthermore, regulators’ inspection-based approach to auditing and approving manufacturing facilities has nurtured an attitude of non-transparency in the industry. Why collect and expose more data and information than is absolutely necessary to pass a compliance audit? Similarly, in the case of CMOs, why provide more information than the customer demands?
A quality-focused culture
Pharma manufacturers must fundamentally reimagine their entire concept of quality. Certainly, the ultimate goal is assuring patients that every pill they take contains the required amount of active ingredient and meets specified quality attributes. Testing 100 percent of pills would achieve that goal, but the quality-by-test approach is not considered viable. The cGMPs — and the more recent focus on quality by design — speak to a more holistic approach, demanding quality in every aspect.
However, despite all the common-sense discussion and comprehensive guidelines around quality, the reality is that pharma has not taken the necessary steps to implement a holistic 21st century approach. The maxim “trust but verify” comes to mind. Today’s cGMP- and compliance-based approach to quality is heavily weighted toward the “trust” side of that statement. To move aggressively toward the “verify” side, the industry must make a quantum leap in its use of modern technologies to enable real-time verification of every aspect of manufacturing. That means putting into practice concepts pharma has discussed for the past 20 years such as:
- Right first time
- Lean and Six Sigma
- Quality by design (QbD)
- Real-time release
- Process analytical technology (PAT)
- Continuous improvement
There is significant pent-up demand for change, both within and outside the industry. For example, consider the FDA’s 2004 publication, “PAT: A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.” This much-discussed guidance noted the need for an integrated systems approach across the product lifecycle. To achieve that objective, the industry must digitize its business processes. That starts with initial process development in R&D and continues through tech transfer to commercial, and to manufacturing itself.
The suite of digital tools that must be implemented immediately includes:
- Digital process design and simulation, spanning the complete product lifecycle
- Comprehensive shop-floor instrumentation
- End-to-end recipe-based process control and automation
- Real-time, automated product review and release
- Advanced process analytics
What should pharma quality look like?
Paper-based batch records should be eliminated completely. They served a purpose prior to the digital age, but simply do not provide the kind of data needed to support a 21st century quality manufacturing entity. The cGMPs must be updated to require manufacturers to deploy the technologies needed on the shop floor to ensure batch records digitally capture every process measurement and event. That would support the basic requirement of electronic batch review and release. The data should also be readily contextualized to enable advanced process analytics, with the goal of increasing process understanding to maximize production efficiency and quality. These requirements should apply equally to all manufacturing entities, including pharma’s internal facilities and their contract manufacturers.
As in the discrete world, tech transfers should leverage digital design tools whose modeling capabilities simulate real-world manufacturing processes before committing to production. On the back end, actual process history should be instantly available for comparison with design expectations, and to update simulation models based on empirical data. This approach would liberate scientists and engineers from paper- and document-based tasks and arm them with the tools to exploit their ingenuity in innovating new and better process designs.
Ultimately, the primary objective would shift from regulatory compliance to quality assurance. Under this new paradigm, compliance would be a byproduct of a culture focused first and foremost on achieving the highest possible standard for product quality.