GMP: The Phoenix Rising from the Contergan Scandal

Good Manufacturing Practice (GMP) refers to a set of broad, legally enforceable recommendations [1] that provide guidelines to manufacturers, packagers, and processors of pharmaceuticals, foods and beverages, medical devices, cosmetics, and nutritional supplements in order to ensure that these products are fit for human consumption (safe) and serve their intended purpose (effective) [2].

Also called cGMP wherein the ‘c’ stands for ‘current,’ the term underscores the need for manufacturers to stay updated with latest GMP practices. Companies execute GMPs through their Quality Management System (QMS) [2]. Considering the comprehensive and exhaustive nature of GMPs, the QMS has to take all departments on board [3].

Now, the reason why GMPs are so demanding lies in its history – GMPs evolved in the wake of the infamous “Contergan Scandal.” Contergan was the brand name under which a German company sold Thalidomide [4]. The chemical was fairly popular among expectant mothers in Europe for countering morning sickness and sleeplessness [5].

They woke up to the horrendous side effects of thalidomide when researchers established the connection between the chemical and severe birth defects in 10,000 infants [6]. Other estimates place the figure higher and regard this as the second largest manmade catastrophe, war being the first [4].

Thalidomide products were almost distributed in the United States! It was only the incessant efforts of vigilant activists that got the chemical banned in 1962, at the eleventh hour [5]. A positive fallout of the disaster was an invigorated public opinion that spurred regulators into issuing the first set of GMPs in 1963. Thereafter, GMPs have expanded steadily to include more products and devices.

With this as the context, it is easy to see why GMPs seek to guarantee that products are [2]:

  • Safe for the end user.
  • Made to a quality that is maintained over the long term.
  • Manufactured by properly trained personnel.
  • Contamination free.
  • Produced via clearly documented processes.
  • Subjected to multiple quality checks at different stages of manufacture.

Regulatory agencies in charge of awarding licences for the production and sale of the above mentioned products issue guidelines that serve as the basis for GMP [2]. Most GMPs provide a free hand to manufacturers for optimizing implementation. Manufacturers can and do utilize this room to harness innovative and cutting edge technologies for better execution of GMPs [6].

Applied correctly, GMPs avoid mix-ups, contamination, deviations, and errors [1]. Over a period of time, the company builds a positive reputation. However, violation of GMPs can invite seizure, recall of the defective goods, financial penalties, or, worse, prison term [1]. Not to mention the costly and lengthy litigation that erodes the company’s brand.

 

Nature of GMPs: Extensive Coverage with Intensive Checks

As mentioned, successful GMP execution requires coordinated efforts from every company department. GMP coverage, therefore, extends across the organization. Moreover, GMPs are intensive – they prescribe what every man and machine must do during different stages, down to the last detail.

Generally speaking, customers cannot judge the quality and efficacy of a product just by looking at it, touching it, or smelling it. This creates the need for quality control. The competent authority has to examine products and stamp them as safe and effective before distribution can begin.

Now, the problem with most quality testing procedures is they check only a small number of samples. Say, for example, ten beverage bottles in a batch of 10,000. The remaining 9,990 are “assumed” to be of the same acceptable quality. It may so happen that a couple of these 9,990 turn out to be defective. This is an inherent limitation of the approach.

And, this is precisely the snag that GMPs seek to overcome. To do so, they get right to the bottom of it. By prescribing norms for every machine and every stage of production, GMPs guarantee that the design, supervision, and control of all production plants and processes are not just correct but painstakingly accurate [6].

Deviation by a meagre whisker is more than enough a reason for disapproval!

But, there is more. GMPs define the hygiene levels of the plant and the people therein, the qualifications of employees involved in the production process, the quality of raw materials used, and testing standards and how to make them consistent.

In a nutshell, GMPs establish steep benchmarks for anything and everything related to the production process. With the framework laid down on such a crystal clear and solid foundation, the manufacturing process has to invariably churn out products of standard quality, purity, identity, and strength [6]. No exceptions whatsoever.

Summing up, cGMPs focus on [1][6][7]:

  • Plant location
  • Equipment validation, calibration, cleaning, and maintenance
  • Process validation
  • Laboratory control
  • Hygiene of plant, equipment, and personnel
  • Personnel qualifications
  • Strong quality control and quality management
  • Quality deviation detection at across production stages
  • Information technology and computer systems
  • Record keeping
  • Change control
  • Raw material standards
  • Dependable testing conditions
  • Vendor eligibility
  • Management and design analysis
  • Product labelling and packing
  • Complaint handling
  • Comprehensive corrective and preventive actions (CAPAs)

While confirmation with ISO standards is voluntary, GMPs are not so lenient [6]. Manufacturers have to comply with them lest there be another tragedy of the Contergan type. Most standards require confirmation to similar requirements. What differ are the recommended benchmarks [6].

 

Other, similar practices, collectively termed GxP, include [2]:

  • Good Laboratory Practice (GLP): for labs engaged in studies of a non-clinical nature.
  • Good Clinical Practice (GCP): covers clinicians and hospitals dealing with clinical trials of novel medicines on humans.
  • Good Pharmacovigilance Practice (GVP): ensures safety of produced medicines.
  • Good Distribution Practice (GDP): advises on how to best distribute medicines meant for humans.
  • Good Agricultural Practice (GAP): recommends procedures for ranches and farms.
  • Good Regulatory Practice (GRP): provides counsel on how to manage regulatory procedures, responsibilities, and paperwork.
  • Good Tissue Practices
  • Good Guidance Practices

 

Equipment Validation @ GMP

Qualification and Validation are two related processes. While qualification records evidence that an equipment/facility/system can perform its intended function, validation examines its capacity to repeatedly deliver the desired output [8]. Validation verifies each significant stage in the production process at the defined conditions [8]. While third parties or suppliers can conduct some parts of the qualification process, companies making equipment for the food and pharmaceutical industry must [8]:

  • Define policies for qualification and validation of equipment and systems.
  • Conduct qualification/validation as per approved and predetermined principles.
  • Include production equipment in the defined policies.
  • Establish higher degree of qualification for more important equipment.
  • Base number of qualification steps on the equipment type.
  • Maintain equipment documents viz. certificates, specifications, and manuals.
  • Validate integral systems before equipment validation.
  • Qualify equipment before operation; regularly qualify existing equipment.
  • • Re-qualify modified equipment.

 

Manufacturing companies deal with four types of qualifications for equipment:

  1.  Design Qualification mandates:
    • Including the end user’s perspective in the design process.
    • Choosing an appropriate vendor for equipment supply.
  2.  Installation Qualification is based on design specifications [9] and requires:
    • Installation as per qualification protocol and plan [8].
    • Integration with other equipment/systems [9].
    • Employing international/national standards for calibration, measurement, and control.
    • Factoring in maintenance, calibration, and cleaning requirements.
    • Recording every equipment detail viz. installation date, supplier, spares, serial number, model, certificates.
    • Considering all sub parts of the equipment/system [8].
  1.  Operational Qualification is premised on functional specifications [9], and mandates:
    • System/equipment operation as per the protocol for operational qualification, particularly in “worst cases” i.e. at the extreme ends of the operational range [8].
    • Equipment to follow the defined sequence of operations [9].
    • Identifying critical components and checking operation of all equipment/system components.
    • Technician/personnel training.
    • Finalized and ratified standard operating procedures (SOPs).
    • Documented records of the acceptable operation.
    • Permitting regular use of equipment that meets operational qualification [9].
  1.  Performance Qualification checks compliance with user specifications [9] and asks for:
    • Performance verification as per performance qualification protocol.
    • Manufacturer to explain need for all performance qualifications.
    • Consistent equipment/system performance in sync with design specifications.
    • Record keeping of all performance verifications.

Other, related points include [9]:

  • Factory Acceptance Testing (FAT) and Site Acceptance Test (SAT) both verify equipment performance as per the end user’s specifications. The venue for FAT is the manufacturer’s factory, while that for SAT is the end user’s plant. SAT evaluates if transportation had affected the equipment.
  • Cleaning considerations:
    • Equipment surfaces that touch in-process material must not be reactive and not come in contact with lubricants, coolants, oil etc.
    • Equipment location must allow access for convenient cleaning.
    • Identification of critical equipment.
    • Defined procedures, tools, and cleaning solutions complete with required durations and concentrations.
    • Fixing responsibility for cleaning and verification of the same.
    • Record keeping.

 

Finally

Effective compliance with GMP is possible only if all company divisions are on board. In a way, GMP tunes all employees to the same frequency. From the point of view of efficient management, it doesn’t get any better than this!

Buffalo Extraction Systems supports the North American & Canandian clientele across a diverse range of extraction systems supplying GMP-compliant equipment to pharmaceutical and food companies.

Our personnel engage with clients across the design, manufacturing, factory acceptance testing (FAT), on-site installation, and the final site acceptance testing (SAT) stages, while providing all documentation for FDA approval.

Contact us at info@buffaloextracts.com and experience the delight of seamless services.

 


 

References

  1.  https://ispe.org/initiatives/regulatory-resources/gmp/what-is-gmp
  2.  https://en.wikipedia.org/wiki/Good_manufacturing_practice
  3.  https://www.elpro.com/leading-minds-network/detail/lessons-of-gmp-failures-why-its-everyones-business/
  4.  https://www.theguardian.com/society/2014/nov/14/-sp-thalidomide-pill-how-evaded-justice
  5.  http://biomanufacturing.org/uploads/files/305429596362804820-brief-history-of-gmps.pdf
  6.  http://outbreaknewstoday.com/introduction-and-importance-of-cgmp-compliance-40205/
  7.  https://www.pharmaknowledgecentre.com/gmp-a-crucial-figure-of-pharma-industry/
  8.  https://www.lfatabletpresses.com/articles/gmp-qualifications-validations-pharmaceutical-world
  9.  https://www.fda.gov/media/92841/download