Inside IPEC: Good Distribution Practices for Pharmaceutical Excipients

Good manufacturing practice (GMP) for pharmaceutical products is well established and incorporated in European Union regulations. And thanks to the International Conference on Harmonization's Q7 guideline, active pharmaceutical ingredients (APIs) also have standard GMPs worldwide. There is still no legal requirement in Europe, however, for GMP or GDP (good distribution practice) compliance regarding pharmaceutical excipients. The lack of regulation in this area is surprising given that most pharmaceutical products contain excipients.

There are still too many examples of recorded deaths due to the use of adulterated or mislabeled pharmaceutical excipients. In 2006, in Panama, for example, nearly 100 people died after taking cough syrup that contained glycerine that had been contaminated with diethylene glycol. The contaminated product was produced in Hengxiang, China, and traveled through several distributors, including one in Barcelona, before entering Panama at the site of the drug manufacturer.

In this case, too many stakeholders involved in the supply chain seemed to simply close their eyes when it came to understanding the way excipients should be managed. This lack of knowledge, control, and traceability is still a major concern, made worse by the fact that many excipients are purchased through agents and brokers on the open (commodity) market.

GDPs for excipients

The supply chain of a pharmaceutical excipient starts at the point of manufacture and continues until used by the finished-product manufacturer. Other parties may be involved in the chain as well, including distributors, transporters, warehousing companies, forwarding agents, traders, and brokers. Although some of these parties do not have direct contact with the product (e.g., transporters), those that do (e.g., repackagers, processers, samplers ) require a higher level of control and GDPs.

Because excipients are often produced in different grades and sold for many applications such as for food, cosmetics, and personal care products, they are traditionally handled as either technical or industrial-grade materials. In fact, because excipient usage for pharmaceutical products makes up a small percentage of the total volume of excipients manufactured, not all excipient manufacturers and distributors are aware of, or recognize, the specific requirements of a pharmaceutical product containing an excipient when it comes to quality and functionality. Most quality-management systems are based on the International Organization for Standardization's ISO 9001, which does not incorporate critical GMP and GDP principles such as cross-contamination and change control, guarantee of traceability, comprehensive sampling and testing, hygiene, cleaning, or documentation.

Parties involved with food and feed applications have implemented risk-based quality systems based on principles of hazard analysis and critical control points (HACCP) as described by the World Health Organization (WHO). HACCP principles, however, also do not fully cover excipient GMP and GDP principles.

In January 2004, therefore, the International Pharmaceutical Excipients Council of Europe (IPEC–Europe) began work on a new guide through its GDP Committee, in conjunction with IPEC–Americas and support from the Japanese Pharmaceutical Excipients Council (JPEC) and WHO. Although the guide is based on WHO's good trade and distribution practices for pharmaceutical starting materials (1), the IPEC guide is more specific, focusing on the "how to" for pharmaceutical excipients.

The final guide, IPEC Good Distribution Practices Guide for Pharmaceutical Excipients, was published in early 2006 and provides a custom quality system for the pharmaceutical excipients' supply chain, incorporating GDP principles and reflecting specific processes for excipient distribution (2). Because of the variety of activities involved in the excipient supply chain, a matrix of applicability for various parties and activities is included. Overall, the guide is meant to help ensure full traceability of pharmaceutical excipients and to prevent contamination and cross-contamination in the supply chain.

The IPEC guide chapters cover the following processes: quality management, organization and personnel, premises, warehousing and storage, equipment, documentation, contract activities, repackaging and relabeling, complaints, recalls, returned goods, handling of nonconforming materials, and dispatch and transport. The following section describes these basic GDP recommendations in more detail.

GDP recommendations

Today, a quality management system such as ISO 9001 is standard throughout industry. A quality management system in accordance with GDP principles is not completely different, but has more focus on certain elements as described herein.

Organization and personnel focuses on qualification and approval of personnel for certain operations and adequate personnel hygiene procedures due to the nature and use of the products. Due to the specific application of excipients and the requirements of GDP principles, personal resources and the extent of training have to be adapted to the activities carried out.

Warehousing and storage covers an important activity carried out by many distributors as well as contract service partners. It is important to ensure that all processes and storage conditions (e.g., pest control, temperature, humidity, and segregation) are well defined and controlled to avoid any deterioration of product quality during the storage period, or any mix up. Links to related processes such as loading and unloading should be considered to avoid any adverse effect on the product.

Equipment highlights that equipment critical to product quality should be designed, installed, used, and maintained under full control. This approach takes into consideration that many equipment failures or a lack of cleanliness can have a detrimental effect on product quality. In addition to the recommendation to use dedicated equipment for product handling, guidance is given on how to design and control cleaning processes.

Documentation is a very important element of many GDP processes. Written procedures and complete records are crucial for the design of robust and consistent processes and for traceability of all operations. Therefore, in this chapter, essential document control processes are described. Beyond that, specific types of documents and their content are emphasized. Certificates of analysis (COA), for example, provide important information throughout the supply chain. The consistency of all associated documents and authenticity of recorded data are essential to ensure adequate control. Therefore, transcription of data, traceability to the original manufacturer's COA, batch integrity, and submission of such information are part of the guidance in this chapter. Another important documentation aspect is that associated with product labels. The reliability of the information on labels contributes significantly to the safe use of excipients. The control of label content and label generating systems has to be a documented process in a GDP system.

Repackaging and relabeling processes are performed by many distributors. Because these processes are considered to be manufacturing processes, the IPEC–PQG GMP Guidelines for Pharmaceutical Excipients (3) are referenced at this point in the GDP Guide. Nevertheless, not all parts of the GMP guide apply to distribution operations. To give guidance for distributors, specific processes are outlined in this section. For repackaging and relabeling operations, special attention should be given to the prevention of contamination and mix-up, hygiene, batch integrity, label control, and sampling. Although this is not a complete list, it shows that where excipients are exposed to the environment and compromise quality, several processes must be installed and maintained. In addition to the design of adequate processes, considerations also should be given to the appropriate repackaging environment, which may differ by product and application (e.g., clean areas, controlled environments). Control of packaging material quality comprises the quality of primary packaging components delivered by suppliers as well as their possible re-use. Both processes may significantly impact quality if not under control; GDP therefore requires documented processes and thorough controls. Labeling processes are considered manufacturing processes and should be designed and controlled as such. Batches should be formally released before further distribution.

Stability considerations should not be forgotten, specifically when excipients are repackaged into containers different from the packaging material used by the original manufacturer of the products. Generally, GDP requires appropriate analytical testing accompanying repackaging activities to demonstrate ongoing consistent product quality.

Complaints handling following GDP principles focus on systematic investigation of root causes and the documented definition of corrective and preventive actions. Furthermore, a risk-evaluation process of the affected batch and other batches must be part of the process to decide whether there is a risk to consumer health, ultimately requiring a recall. Communication with customers and original producers are required actions as part of complaint handling under GDP.

Recall is another crucial part of a GDP quality system. Recalls are not common in other quality systems. A recall process should be implemented to ensure that in the case of a product defect, all implicated material has to be withdrawn from the market to avoid any potential adverse effect to consumers.

Returned goods are excipients a distributor receives back due to recalls, complaints, or other reasons. Such material should be quarantined and fully investigated before any consideration is made regarding the goods' rejection or re-use. This process should be fully documented.

Dispatch and transportation is the final step in the excipient supply chain. This process has the same potential impact on product quality as warehousing and/or repackaging. All transport processes should be designed and documented in the same way as warehousing processes. This should include a focus on prevention of product deterioration through adequate transport conditions, maintenance/full traceability of appropriate shipping documentation, and adequate flow of all relevant information (e.g., conditions for storage and transportation, original manufacturer). In case products are transported in bulk tanks, special procedures should be in place to avoid contamination of the products by transport equipment. These procedures should include documented control and maintenance of the equipment (e.g. bulk trucks, seals, hoses, pumps), defined and documented cleaning procedures, and restricted prior-cargos. The use of dedicated equipment has to be considered as the best solution.

Contract activities are activities contracted out to a third party and may include laboratory analysis or transportation. In these cases, GDP requires written contracts to be in place between the distributor and the contractor. Thorough evaluation and control of contractors, including auditing, should ensure that contractors follow the same GDP principles.

GDP auditing

In 2008, the IPEC–Europe GDP committee published the IPEC Good Distribution Practices Audit Guideline for Pharmaceutical Excipients as another tool to evaluate the practice and quality systems of those parties involved in the supply chain of pharmaceutical excipients (3). The audit guideline provides auditors with a questionnaire containing almost 250 questions that reflect all the elements of the GDP guide. Intended to provide a framework for the auditor who must always decide the scope of an audit, the guideline can also be used as a self-assessment questionnaire to be completed by a distributor or supplier, or as an audit checklist.

IPEC–Europe has used many of the questions from the Safety and Quality Assessment Scheme–SQAS Distributor (ESAD II, primarily section F and subsection G) questionnaire to achieve close harmonization with this document already widely used by European distributors of chemicals (2, 4).

Future directions

By applying the principles of the IPEC GDP guide and audit guideline, along with GMPs, manufacturers and distributors can attain an appropriate level of control at all stages of the manufacturing and distribution process. In addition, the IPEC GDP audit guideline can aid the auditing process when a manufacturer is working with a pharmaceutical excipient distributor.

Looking ahead, the European Commission is working on legislation for identified "certain" pharmaceutical excipients, which may lead to legal enforcement of GDP principles. In the US, IPEC–Americas and the Food and Drug Administration are in discussions regarding the implementation of an excipient pedigree that would require pharmaceutical dosage-form manufacturers to be aware and knowledgeable of the complete supply chain of the excipients they use. Specific requirements are defined in TriPEC's Excipient Pedigree position paper for excipient manufacturers, distributors, and users. There is also an initiative driven by IPEC–Europe and the European Fine Chemicals Group to implement a certification scheme for producers and distributors of pharmaceutical excipients. The scheme will be based on ISO 9001 with additional requirements taken from IPEC's GMP and GDP guides. The final documents will be invaluable to drug manufacturers, distributors, and suppliers who wish to manage risk and ensure their products are safe for the patient.

The Good Distribution Practice (GDP) Committee of the International Pharmaceutical Excipients Council of Europe (IPEC–Europe) consists of the following members: Mathias Brenken at Dow Deutschland, Andreas Lekebusch at Biesterfeld Spezialchemie, Wilhelm Gierling at Brenntag Holding, Steve Hewitt at sanofi-aventis, and Allan Whiston at QA Resolutions, and Frank Milek at Aug. Hedinger, tel. +49 711 402050, fmilek@hedinger.de

References

1. WHO Expert Committee on Specifications for Pharmaceutical Preparations, "Annex 2: Good Trade and Distribution Practices for Pharmaceutical Starting Materials," in WHO Tech. Rept. Series, No. 917 (38), 2003.

2. IPEC, IPEC GDP Guide for Pharmaceutical Excipients (2006).

3. IPEC, IPEC GDP Audit Guideline for Pharmaceutical Excipients (2008).

4. CEFIC and FECC, European Single Assessment Document for Chemical Distributors, Appendix B (Brussels, 1999), Rev. 2003, 2006.

Appendix

Guidance documents related to good manufacturing and distribution practices (GMP, GDP) of pharmaceutical starting materials

1. CEFIC, Guidelines for Handling and Distribution of Propylene Glycol USP/EP (1999), Revision 1 in 2003, Revision 1.1. in 2006, Revision 2 under development. Industry code of best practice guidelines, created by the European manufacturers of propylene glycol.

2. CEFIC and FECC (European Association of Chemical Distributors), European Single Assessment Document for Chemical Distributors (ESAD), Appendix B for Food, Pharma and/or Cosmetic Products (1999), Revised in 2003 and 2006 (SQAS-Distributor, Appendix F and subsection G for pharmaceutical excipients added in latest revision). Third party assessment scheme with questionnaires and guidance document.

3. WHO Expert Committee on Specifications for Pharmaceutical Preparations, Good Manufacturing Practices—Supplementary Guidelines for the Manufacture of Pharmaceutical Excipients, Annex 5, WHO Technical Report Series, No. 885 (Geneva, 1999).

4. ICH, Q7: Good Manufacturing Practices Guide for Active Pharmaceutical Ingredients (Geneva, 2000). Chapter 17 defines specific requirements for distributors of APIs. This globally harmonized document has been overtaken in European legislation as GMP Annex 18 (2001), and published as Part II of the European Union's Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use—Basic Requirements for Active Substances used as Starting Materials (2005).

5. IPEC, Good Manufacturing Practices Audit Guideline for Distributors of Bulk Pharmaceutical Excipients and guidance for excipient distributors IS THIS THE ACCURATE TITLE?, based on IPEC's 1997 Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients (2000). This guideline has been replaced by the organization's GDP 2008 audit guide.

6. WHO Expert Committee on Specifications for Pharmaceutical Preparations, Good Trade and Distribution Practices for Pharmaceutical Starting Materials, WHO Technical Report Series, No. 917 (Geneva, 2003). This document provides general principles of good practices in the supply chain of pharmaceutical starting materials (APIs and excipients),

7. IPEC, Joint IPEC-PQG Good Manufacturing Practice Guide for Pharmaceutical Excipients (2006). The second revision of this comprehensive guide was first published in 1995, revised 2001 to align with ISO 9001:2000, and revised again in 2006 as a joint venture with the Pharmaceutical Quality Group.

8. IPEC, IPEC Good Distribution Practices Guide for Pharmaceutical Excipients (2006). Explanatory document to WHO's GTDP guideline, providing detailed "how to" guidance for supply chain operations of excipients.

9. IPEC, IPEC Good Distribution Practices Audit Guideline for Pharmaceutical Excipients (2008). GDP audit guide based on the SQAS-Distributor (ESAD II) assessment scheme, with additional questionnaire questions.